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1
Bittman, Kevin S. "Immune Cell Metabolic Fitness for Life." Antibodies 11, no. 2 (April 30, 2022): 32. http://dx.doi.org/10.3390/antib11020032.
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Adoptive cell therapy holds great promise for treating a myriad of diseases, especially cancer. Within the last decade, immunotherapy has provided a significant leap in the successful treatment of leukemia. The research conducted throughout this period to understand the interrelationships between cancer cells and infiltrating immune cells winds up having one very common feature, bioenergetics. Cancer cells and immune cells both need ATP to perform their individual functions and cancer cells have adopted means to limit immune cell activity via changes in immune cell bioenergetics that redirect immune cell behavior to encourage tumor growth. Current leading strategies for cancer treatment super-charge an individual’s own immune cells against cancer. Successful Chimeric Antigen Receptor T Cells (CAR T) target pathways that ultimately influence bioenergetics. In the last decade, scientists identified that mitochondria play a crucial role in T cell physiology. When modifying T cells to create chimeras, a unique mitochondrial fitness emerges that establishes stemness and persistence. This review highlights many of the key findings leading to this generation’s CAR T treatments and the work currently being done to advance immunotherapy, to empower not just T cells but other immune cells as well against a variety of cancers.
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Derbal, Youcef. "Cell Adaptive Fitness and Cancer Evolutionary Dynamics." Cancer Informatics 22 (January 2023): 117693512311546. http://dx.doi.org/10.1177/11769351231154679.
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Genome instability of cancer cells translates into increased entropy and lower information processing capacity, leading to metabolic reprograming toward higher energy states, presumed to be aligned with a cancer growth imperative. Dubbed as the cell adaptive fitness, the proposition postulates that the coupling between cell signaling and metabolism constrains cancer evolutionary dynamics along trajectories privileged by the maintenance of metabolic sufficiency for survival. In particular, the conjecture postulates that clonal expansion becomes restricted when genetic alterations induce a sufficiently high level of disorder, that is, high entropy, in the regulatory signaling network, abrogating as a result the ability of cancer cells to successfully replicate, leading to a stage of clonal stagnation. The proposition is analyzed in the context of an in-silico model of tumor evolutionary dynamics to illustrate how cell-inherent adaptive fitness may predictably constrain clonal evolution of tumors, which would have significant implications for the design of adaptive cancer therapies.
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Skums, Pavel, Viachaslau Tsyvina, and Alex Zelikovsky. "Inference of clonal selection in cancer populations using single-cell sequencing data." Bioinformatics 35, no. 14 (July 2019): i398—i407. http://dx.doi.org/10.1093/bioinformatics/btz392.
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Abstract Summary Intra-tumor heterogeneity is one of the major factors influencing cancer progression and treatment outcome. However, evolutionary dynamics of cancer clone populations remain poorly understood. Quantification of clonal selection and inference of fitness landscapes of tumors is a key step to understanding evolutionary mechanisms driving cancer. These problems could be addressed using single-cell sequencing (scSeq), which provides an unprecedented insight into intra-tumor heterogeneity allowing to study and quantify selective advantages of individual clones. Here, we present Single Cell Inference of FItness Landscape (SCIFIL), a computational tool for inference of fitness landscapes of heterogeneous cancer clone populations from scSeq data. SCIFIL allows to estimate maximum likelihood fitnesses of clone variants, measure their selective advantages and order of appearance by fitting an evolutionary model into the tumor phylogeny. We demonstrate the accuracy our approach, and show how it could be applied to experimental tumor data to study clonal selection and infer evolutionary history. SCIFIL can be used to provide new insight into the evolutionary dynamics of cancer. Availability and implementation Its source code is available at https://github.com/compbel/SCIFIL.
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Giannarelli, Chiara. "Loss of TET2 boosts cell fitness." Science Translational Medicine 12, no. 553 (July 22, 2020): eabd3619. http://dx.doi.org/10.1126/scitranslmed.abd3619.
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George, Bijesh, P. Mukundan Pillai, Aswathy Mary Paul, Revikumar Amjesh, Kim Leitzel, Suhail M. Ali, Oleta Sandiford, et al. "Cellular Fitness Phenotypes of Cancer Target Genes from Oncobiology to Cancer Therapeutics." Cells 10, no. 2 (February 18, 2021): 433. http://dx.doi.org/10.3390/cells10020433.
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To define the growing significance of cellular targets and/or effectors of cancer drugs, we examined the fitness dependency of cellular targets and effectors of cancer drug targets across human cancer cells from 19 cancer types. We observed that the deletion of 35 out of 47 cellular effectors and/or targets of oncology drugs did not result in the expected loss of cell fitness in appropriate cancer types for which drugs targeting or utilizing these molecules for their actions were approved. Additionally, our analysis recognized 43 cellular molecules as fitness genes in several cancer types in which these drugs were not approved, and thus, providing clues for repurposing certain approved oncology drugs in such cancer types. For example, we found a widespread upregulation and fitness dependency of several components of the mevalonate and purine biosynthesis pathways (currently targeted by bisphosphonates, statins, and pemetrexed in certain cancers) and an association between the overexpression of these molecules and reduction in the overall survival duration of patients with breast and other hard-to-treat cancers, for which such drugs are not approved. In brief, the present analysis raised cautions about off-target and undesirable effects of certain oncology drugs in a subset of cancers where the intended cellular effectors of drug might not be good fitness genes and that this study offers a potential rationale for repurposing certain approved oncology drugs for targeted therapeutics in additional cancer types.
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Ferrari, Adam James, Ronny Drapkin, and Rajan Gogna. "Cell Fitness: More Than Push-Ups." International Journal of Molecular Sciences 22, no. 2 (January 7, 2021): 518. http://dx.doi.org/10.3390/ijms22020518.
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Cell competition (CC) is a feature that allows tumor cells to outcompete and eliminate adjacent cells that are deemed less fit. Studies of CC, first described in Drosophila melanogaster, reveal a diversity of underlying mechanisms. In this review, we will discuss three recent studies that expand our understanding of the molecular features governing CC. In particular, we will focus on a molecular fitness fingerprint, oncogenic pathways, and the importance of cell junction stability. A fitness fingerprint, mediated by flower (hFWE) protein isoforms, dictates that cells expressing the flower-win isoforms will outcompete adjacent flower-loss-expressing cells. The impact of the flower protein isoforms is seen in cancer progression and may have diagnostic potential. The yes-associated protein (YAP) and TAZ transcription factors, central mediators of the oncogenic Hippo pathway, elevate peritumoral fitness thereby protecting against tumor progression and provide a suppressive barrier. Similarly, COL17A1 is a key component in hemidesmosome stability, and its expression in epidermal stem cells contributes to fitness competition and aging characteristics. The contributions of these pathways to disease development and progression will help define how CC is hijacked to favor cancer growth. Understanding these features will also help frame the diagnostic and therapeutic possibilities that may place CC in the crosshairs of cancer therapeutics.
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Lawlor, Katerina, Salvador Pérez-Montero, Ana Lima, and Tristan A. Rodríguez. "Transcriptional versus metabolic control of cell fitness during cell competition." Seminars in Cancer Biology 63 (June 2020): 36–43. http://dx.doi.org/10.1016/j.semcancer.2019.05.010.
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Nunney, Leonard, and Kevin Thai. "Determining cancer risk: the evolutionary multistage model or total stem cell divisions?" Proceedings of the Royal Society B: Biological Sciences 287, no. 1941 (December 16, 2020): 20202291. http://dx.doi.org/10.1098/rspb.2020.2291.
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A recent hypothesis proposed that the total number of stem cell divisions in a tissue (TSCD model) determine its intrinsic cancer risk; however, a different model—the multistage model—has long been used to understand how cancer originates. Identifying the correct model has important implications for interpreting the frequency of cancers. Using worldwide cancer incidence data, we applied three tests to the TSCD model and an evolutionary multistage model of carcinogenesis (EMMC), a model in which cancer suppression is recognized as an evolving trait, with natural selection acting to suppress cancers causing a significant mean loss of Darwinian fitness. Each test supported the EMMC but contradicted the TSCD model. This outcome undermines results based on the TSCD model quantifying the relative importance of ‘bad luck' (the random accumulation of somatic mutations) versus environmental and genetic factors in determining cancer incidence. Our testing supported the EMMC prediction that cancers of large rapidly dividing tissues predominate late in life. Another important prediction is that an indicator of recent oncogenic environmental change is an unusually high mean fitness loss due to cancer, rather than a high lifetime incidence. The evolutionary model also predicts that large and/or long-lived animals have evolved mechanisms of cancer suppression that may be of value in preventing or controlling human cancers.
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Jiang, Xiaowei, and Ian P. M. Tomlinson. "Why is cancer not more common? A changing microenvironment may help to explain why, and suggests strategies for anti-cancer therapy." Open Biology 10, no. 4 (April 2020): 190297. http://dx.doi.org/10.1098/rsob.190297.
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One of the great unsolved puzzles in cancer biology is not why cancers occur, but rather explaining why so few cancers occur compared with the theoretical number that could occur, given the number of progenitor cells in the body and the normal mutation rate. We hypothesized that a contributory explanation is that the tumour microenvironment (TME) is not fixed due to factors such as immune cell infiltration, and that this could impair the ability of neoplastic cells to retain a high enough fitness to become a cancer. The TME has implicitly been assumed to be static in most cancer evolution models, and we therefore developed a mathematical model of spatial cancer evolution assuming that the TME, and thus the optimum cancer phenotype, changes over time. Based on simulations, we show how cancer cell populations adapt to diverse changing TME conditions and fitness landscapes. Compared with static TMEs, which generate neutral dynamics, changing TMEs lead to complex adaptations with characteristic spatio-temporal heterogeneity involving variable fitness effects of driver mutations, subclonal mixing, subclonal competition and phylogeny patterns. In many cases, cancer cell populations fail to grow or undergo spontaneous regression, and even extinction. Our analyses predict that cancer evolution in a changing TME is challenging, and can help to explain why cancer is neither inevitable nor as common as expected. Should cancer driver mutations with effects dependent of the TME exist, they are likely to be selected. Anti-cancer prevention and treatment strategies based on changing the TME are feasible and potentially effective.
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Rozhok, Andrii I., and James DeGregori. "Toward an evolutionary model of cancer: Considering the mechanisms that govern the fate of somatic mutations." Proceedings of the National Academy of Sciences 112, no. 29 (July 21, 2015): 8914–21. http://dx.doi.org/10.1073/pnas.1501713112.
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Our understanding of cancer has greatly advanced since Nordling [Nordling CO (1953) Br J Cancer 7(1):68–72] and Armitage and Doll [Armitage P, Doll R (1954) Br J Cancer 8(1):1–12] put forth the multistage model of carcinogenesis. However, a number of observations remain poorly understood from the standpoint of this paradigm in its contemporary state. These observations include the similar age-dependent exponential rise in incidence of cancers originating from stem/progenitor pools differing drastically in size, age-dependent cell division profiles, and compartmentalization. This common incidence pattern is characteristic of cancers requiring different numbers of oncogenic mutations, and it scales to very divergent life spans of mammalian species. Also, bigger mammals with larger underlying stem cell pools are not proportionally more prone to cancer, an observation known as Peto’s paradox. Here, we present a number of factors beyond the occurrence of oncogenic mutations that are unaccounted for in the current model of cancer development but should have significant impacts on cancer incidence. Furthermore, we propose a revision of the current understanding for how oncogenic and other functional somatic mutations affect cellular fitness. We present evidence, substantiated by evolutionary theory, demonstrating that fitness is a dynamic environment-dependent property of a phenotype and that oncogenic mutations should have vastly different fitness effects on somatic cells dependent on the tissue microenvironment in an age-dependent manner. Combined, this evidence provides a firm basis for understanding the age-dependent incidence of cancers as driven by age-altered systemic processes regulated above the cell level.
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Baracos, Vickie E., Raul C. Urtasun, Dennis P. Humen, and Robert G. Haennel. "Physical Fitness of Patients with Small Cell Lung Cancer." Clinical Journal of Sport Medicine 4, no. 4 (October 1994): 223–27. http://dx.doi.org/10.1097/00042752-199410000-00002.
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YAO, PENG, SHUTANG WEN, BAOSHUN LI, and YUXIAO LI. "A SIMPLE EVOLUTIONARY MODEL FOR CANCER CELL POPULATION AND ITS IMPLICATIONS ON CANCER THERAPY." Modern Physics Letters B 23, no. 25 (October 10, 2009): 2999–3011. http://dx.doi.org/10.1142/s0217984909021077.
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We established a simple evolutionary model based on the cancer stem cell hypothesis. By taking cellular interactions into consideration, we introduced the evolutionary games theory into the quasispecies model. The fitness values are determined by both genotypes and cellular interactions. In the evolutionary model, a cancer cell population can evolve in different patterns. For single peak intrinsic fitness landscape, the evolution pattern can transit with increasing differentiation probability from malignant cells to benign cells in four different modes. For a large enough value of differentiation probability, the evolution is always the case that the malignant cells extinct ultimately, which might give some implications on cancer therapy.
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Dwane, Lisa, Fiona M. Behan, Emanuel Gonçalves, Howard Lightfoot, Wanjuan Yang, Dieudonne van der Meer, Rebecca Shepherd, Miguel Pignatelli, Francesco Iorio, and Mathew J. Garnett. "Project Score database: a resource for investigating cancer cell dependencies and prioritizing therapeutic targets." Nucleic Acids Research 49, no. D1 (October 17, 2020): D1365—D1372. http://dx.doi.org/10.1093/nar/gkaa882.
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Abstract CRISPR genetic screens in cancer cell models are a powerful tool to elucidate oncogenic mechanisms and to identify promising therapeutic targets. The Project Score database (https://score.depmap.sanger.ac.uk/) uses genome-wide CRISPR–Cas9 dropout screening data in hundreds of highly annotated cancer cell models to identify genes required for cell fitness and prioritize novel oncology targets. The Project Score database currently allows users to investigate the fitness effect of 18 009 genes tested across 323 cancer cell models. Through interactive interfaces, users can investigate data by selecting a specific gene, cancer cell model or tissue type, as well as browsing all gene fitness scores. Additionally, users can identify and rank candidate drug targets based on an established oncology target prioritization pipeline, incorporating genetic biomarkers and clinical datasets for each target, and including suitability for drug development based on pharmaceutical tractability. Data are freely available and downloadable. To enhance analyses, links to other key resources including Open Targets, COSMIC, the Cell Model Passports, UniProt and the Genomics of Drug Sensitivity in Cancer are provided. The Project Score database is a valuable new tool for investigating genetic dependencies in cancer cells and the identification of candidate oncology targets.
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Green, Douglas R. "Health and Fitness at the Single-Cell Level." Cancer Immunology Research 9, no. 2 (February 2021): 130–35. http://dx.doi.org/10.1158/2326-6066.cir-20-0418.
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Levayer, Romain, and Eduardo Moreno. "Mechanisms of cell competition: Themes and variations." Journal of Cell Biology 200, no. 6 (March 18, 2013): 689–98. http://dx.doi.org/10.1083/jcb.201301051.
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Cell competition is the short-range elimination of slow-dividing cells through apoptosis when confronted with a faster growing population. It is based on the comparison of relative cell fitness between neighboring cells and is a striking example of tissue adaptability that could play a central role in developmental error correction and cancer progression in both Drosophila melanogaster and mammals. Cell competition has led to the discovery of multiple pathways that affect cell fitness and drive cell elimination. The diversity of these pathways could reflect unrelated phenomena, yet recent evidence suggests some common wiring and the existence of a bona fide fitness comparison pathway.
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Vivarelli, Silvia, Laura Wagstaff, and Eugenia Piddini. "Cell wars: regulation of cell survival and proliferation by cell competition." Essays in Biochemistry 53 (August 28, 2012): 69–82. http://dx.doi.org/10.1042/bse0530069.
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During cell competition fitter cells take over the tissue at the expense of viable, but less fit, cells, which are eliminated by induction of apoptosis or senescence. This probably acts as a quality-control mechanism to eliminate suboptimal cells and safeguard organ function. Several experimental conditions have been shown to trigger cell competition, including differential levels in ribosomal activity or in signalling pathway activation between cells, although it is unclear how those differences are sensed and translated into fitness levels. Many of the pathways implicated in cell competition have been previously linked with cancer, and this has led to the hypothesis that cell competition could play a role in tumour formation. Cell competition could be co-opted by cancer cells to kill surrounding normal cells and boost their own tissue colonization. However, in some cases, cell competition could have a tumour suppressor role, as cells harbouring mutations in a subset of tumour suppressor genes are killed by wild-type cells. Originally described in developing epithelia, competitive interactions have also been observed in some stem cell niches, where they play a role in regulating stem cell selection, maintenance and tissue repopulation. Thus competitive interactions could be relevant to the maintenance of tissue fitness and have a protective role against aging.
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Merk, D. J., L. Paul, F. Tsiami, H. Hohenthanner, G. Mohseni-Kouchesfahani, B. Walter, L. A. Haeusser, et al. "P07.11.B A NOVEL CRISPR/CAS9 KNOCKOUT LIBRARY UNCOVERS PAN-ESSENTIAL MIRNAS IN HUMAN CANCER CELL LINES." Neuro-Oncology 25, Supplement_2 (September 1, 2023): ii53. http://dx.doi.org/10.1093/neuonc/noad137.171.
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Abstract BACKGROUND MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that play an important role during cancer initiation and progression. Genome-wide functional screening using the CRISPR/Cas9 system is a powerful tool to uncover genetic dependencies for distinct tumor entities, and has revealed novel insights into pan-cancer fitness genes. Current libraries are focused on single guide RNAs (sgRNAs) targeting protein-coding genes, thereby limiting functional genomics-based investigations of miRNA function. MATERIAL AND METHODS We here designed a novel CRISPR/Cas9 knockout library of 8,107 distinct sgRNAs targeting a total of 1,769 human miRNAs. Using a total of 45 human cancer cell lines, representing 16 different tumor entities, we performed negative selection screens to identify miRNA fitness genes. Screen hits per cell line were scored on the basis of a combination of a supervised Bayesian gene essentiality analysis (BAGEL2) and an unsupervised gene ranking algorithm (MAGeCK). miRNA genes that scored across all cell lines, i.e. potentially pan-essential miRNAs, were identified using a combination of the Adaptive Daisy Model (ADaM) algorithm and the Fitness Percentile (FiPer) method. RESULTS In silico analyses revealed that our library has significantly lower off-target activity for protein-coding genes as compared to previously described miRNA-targeting sgRNA libraries, while providing a higher coverage of miRNAs present in the human genome. In total, only 13% (n=230) of all targeted miRNAs induced a fitness effect on one or more cell lines, and the majority (83%) of these genes induced a dependency in less than 50% of the tested cell lines. Pan-cancer fitness gene detection by ADaM or FiPer differed solely on the level of stringency. As such, ADaM and FiPer identified 34 core fitness or 54 common essential miRNAs, respectively, and almost all core fitness genes (97%) were identified as common essential. Preliminary network analyses revealed that protein-coding genes that are regulated by core fitness miRNAs are significantly enriched for cell cycle and p53 signaling networks, providing a first rationale for their dependency profiles in human cancer cell lines. CONCLUSION We here established a novel method for functional investigation of miRNAs by means of genome-wide CRISPR/Cas9 knockout screens. Our sgRNA library outperforms previously established libraries in terms of specificity and overall miRNA coverage, making it a novel tool to investigate miRNA function in a genome-wide fashion. We here use this library to define a first-of-its-kind genome-wide functional annotation of miRNAs, revealing a subset of pan-cancer fitness miRNAs that might regulate essential cellular processes such as cell cycle progression. Our data highlight the wide potential of this library in investigating miRNA function in diverse biological settings.
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Nayak, Sumeet, Jennifer A. Calvo, Ke Cong, Min Peng, Emily Berthiaume, Jessica Jackson, Angela M. Zaino, Alessandro Vindigni, M. Kyle Hadden, and Sharon B. Cantor. "Inhibition of the translesion synthesis polymerase REV1 exploits replication gaps as a cancer vulnerability." Science Advances 6, no. 24 (June 2020): eaaz7808. http://dx.doi.org/10.1126/sciadv.aaz7808.
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The replication stress response, which serves as an anticancer barrier, is activated not only by DNA damage and replication obstacles but also oncogenes, thus obscuring how cancer evolves. Here, we identify that oncogene expression, similar to other replication stress–inducing agents, induces single-stranded DNA (ssDNA) gaps that reduce cell fitness. DNA fiber analysis and electron microscopy reveal that activation of translesion synthesis (TLS) polymerases restricts replication fork slowing, reversal, and fork degradation without inducing replication gaps despite the continuation of replication during stress. Consistent with gap suppression (GS) being fundamental to cancer, we demonstrate that a small-molecule inhibitor targeting the TLS factor REV1 not only disrupts DNA replication and cancer cell fitness but also synergizes with gap-inducing therapies such as inhibitors of ATR or Wee1. Our work illuminates that GS during replication is critical for cancer cell fitness and therefore a targetable vulnerability.
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Arora, Gurpreet Kaur, Ryan Loughran, Kyanh Ly, Cheska Marie Galapate, Alicia Llorente, Taylor R. Anderson, Chantal Pauli, et al. "Abstract C044: PI5P4Kα regulates cell fitness through iron homeostasis in pancreatic cancer." Cancer Research 84, no. 17_Supplement_2 (September 15, 2024): C044. http://dx.doi.org/10.1158/1538-7445.pancreatic24-c044.
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Abstract PI5P4Ks (Phosphatidylinositol 5-phosphate 4-kinases) are a family of lipid kinases that phosphorylate phosphatidylinositol 5-monophosphate (PI-5-P) at the 4-position to generate distinct pools of phosphatidylinositol 4,5-bisphosphate (PI-4,5-P2) largely on intracellular membranes. These lipid species are involved in cellular and metabolic stress responses, signaling and organelle communication. PI5P4Ks have been implicated in multiple cancers, with compelling evidence showing synthetic lethality when PI5P4Ks are inhibited in TP53-mutant cancer cells. Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive metabolic rewiring but despite the critical roles of PI5P4Ks in cellular metabolism, their role in PDAC remains completely unexplored. We have found that depletion of PI5P4Kα selectively induces apoptotic cell death in PDAC cells. To gain insights into the metabolic mechanisms underlying this apoptotic cell death, we quantified polar metabolites using gas chromatography- mass spectrometry (GC/MS) and found significant reductions in the ratio of monounsaturated to saturated fatty acids, lactate and TCA metabolites. Orthogonal rescue assays demonstrated that exogenous supplementation with fatty acids, pyruvate or lactate fail to rescue the observed apoptosis in PI5P4Kα-knockdown cells; however, TCA cycle metabolites did reverse the extent of apoptosis. Interestingly, we identify that these altered metabolic read-outs and the effects on cell fitness are dependent on iron. Consistent with these findings, intracellular iron levels are reduced upon PI5P4Kα inhibition, and this is directly linked to PI5P4Kα depletion disturbing the intracellular labile iron pools via iron import. Using a heterotopic xenograft mouse model, we demonstrate that PI5P4Kα knockdown leads to the abrogation of PDAC tumor growth due to increased intratumoral cell death. Validating the physiological relevance of PI5P4Kα in human PDAC, we find that PIP4K2A, the gene that encodes PI5P4Kα, is upregulated in human PDAC specimens relative to normal pancreas, and that PIP4K2A gene expression is strongly correlated with iron uptake related gene signatures. This study highlights the critical role of PI5P4Kα in PDAC and suggests that PI5P4Kα inhibition has therapeutic potential in pancreatic cancer. Citation Format: Gurpreet Kaur Arora, Ryan Loughran, Kyanh Ly, Cheska Marie Galapate, Alicia Llorente, Taylor R Anderson, Chantal Pauli, David A Scott, Yoav Altman, Cosimo Commisso, Brooke M Emerling. PI5P4Kα regulates cell fitness through iron homeostasis in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C044.
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Castracani, Carlo Castruccio, Lucia Longhitano, Alfio Distefano, Daniela Anfuso, Stavroula Kalampoka, Enrico La Spina, Marinella Astuto, et al. "Role of 17β-Estradiol on Cell Proliferation and Mitochondrial Fitness in Glioblastoma Cells." Journal of Oncology 2020 (February 14, 2020): 1–9. http://dx.doi.org/10.1155/2020/2314693.
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Gliomas are the most common primary tumors of the central nervous system (CNS) in the adult. Previous data showed that estrogen affects cancer cells, but its effect is cell-type-dependent and controversial. The present study aimed to analyze the effects of estradiol (E2, 5 nM) in human glioblastoma multiforme U87-MG cells and how it may impact on cell proliferation and mitochondrial fitness. We monitored cell proliferation by xCELLigence technology and mitochondrial fitness by assessing the expression of genes involved in mitochondrial biogenesis (PGC1α, SIRT1, and TFAM), oxidative phosphorylation (ND4, Cytb, COX-II, COX IV, NDUFA6, and ATP synthase), and dynamics (OPA1, MNF2, MNF1, and FIS1). Finally, we evaluated Nrf2 nuclear translocation by immunocytochemical analysis. Our results showed that E2 resulted in a significant increase in cell proliferation, with a significant increase in the expression of genes involved in various mechanisms of mitochondrial fitness. Finally, E2 treatment resulted in a significant increase of Nrf2 nuclear translocation with a significant increase in the expression of one of its target genes (i.e., heme oxygenase-1). Our results suggest that E2 promotes proliferation in glioblastoma cells and regulate the expression of genes involved in mitochondrial fitness and chemoresistance pathway.
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Shahriyari, Leili. "Cell dynamics in tumour environment after treatments." Journal of The Royal Society Interface 14, no. 127 (February 2017): 20160977. http://dx.doi.org/10.1098/rsif.2016.0977.
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Most cancer treatments cause necrotic cell deaths in the tumour microenvironment. Necrotic cells send signals to immune cells to start the wound healing process in the tissue. Therefore, we assume after stopping treatments there is a wound that needs to be healed. We develop a simple computational model to investigate cell dynamics during the wound healing process after treatments. The model predicts that the involvement of high-fitness cancer cells in the wound healing leads to fast relapse, and cancer cells outside of the wound can cause a slow recurrence of the tumour. Therefore, the absence of relapse after treatments may imply a slow-developing tumour that might not reach an observable size in the patients' lifetime. Additionally, the model indicates that the location of remaining cancer cells after treatments is an important factor in the recurrence time. The fastest recurrence happens when high-fitness cancer cells remain inside of the wound. However, the longest time to recurrence corresponds to cancer cells located outside of the wound. Note that this model is the first attempt to study cell dynamics in the wound healing process after cancer treatments, and it has some limitations that might influence the results. Experiments are needed to validate the results.
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Singh, Balraj, Vanessa N. Sarli, and Anthony Lucci. "Abstract 3385: Modeling evolutionary fitness in resistant cancers based on a common adaptability trait." Cancer Research 84, no. 6_Supplement (March 22, 2024): 3385. http://dx.doi.org/10.1158/1538-7445.am2024-3385.
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Abstract Cancer is composed of a major subpopulation of proliferative cells and a minor subpopulation of highly adaptable cells. Although it is evident that cancer is an evolution like process driven by rare adaptable cancer cells that persist under various selection pressures, most of our knowledge about cancer comes from studying proliferative cancer cells. To overcome the hurdle in modeling adaptable cancer cell state that defeats all currently offered therapies, we are exploiting a linkage that exists between different adaptability substates such as metabolic, regulatory, and structural substates. Our studies, thus far carried out with aggressive triple-negative breast cancer and melanoma cell lines, suggest that it is feasible to apply severe metabolic challenges as realistic selection pressures/bottlenecks for modeling highly abnormal and highly adaptable cancer cells that drive cancer evolution and therapy resistance. The most significant aspect of our approach is an ability to model rare resistant cells (approximately 0.01% of cells) that survive in reversible quiescence under selection pressures. Monitoring of cells under microscope for several weeks under a severe and prolonged metabolic challenge, for example, a lack of glutamine in culture medium, revealed perhaps most interesting and cancer-relevant cells that survive in quiescence for weeks and then advance to generate therapy-resistant cells. Such microscopic monitoring revealed a significant heterogeneity among surviving cells. As examples, 1) surviving cells differ in the depth of quiescence, some cells trying to proliferate sooner than others; 2) as cells progress from quiescence to proliferation, their fate is far from certain: cells may progress to yield few cells, tiny colony, or large colony and then stop proliferating and in most instances die (abortive attempts at evolution). Of significance, the cell lines derived inflammatory breast cancer (IBC), an aggressive subtype of breast cancer, possessed a higher evolutionary fitness than non-IBC cell lines. This approach also eliminates 99.99% of cells that proliferate in cell culture but would not survive selection pressures in the body. The adaptable cells that survived the bottleneck and then proliferated indefinitely were highly resistant and metastatic. Molecular analyses of adaptable cells, including gene expression microarrays, CGH microarrays, and whole genome sequencing revealed mechanisms for their plasticity (exemplified by markers of high EMT), and for generating cellular diversity by altering epigenome (exemplified by low TET2) and by structural modifications in transcriptome (exemplified by high FTO). We conclude that the phenotype-based approach described here is good at modeling deep intrinsic resistance and may be useful in developing strategies for improving outcomes in resistant cancers. Supported by a State of Texas Grant for Rare and Aggressive Cancers. Citation Format: Balraj Singh, Vanessa N. Sarli, Anthony Lucci. Modeling evolutionary fitness in resistant cancers based on a common adaptability trait [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3385.
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Morris, Jessica S., Ahmed Z. Gad, Lea M. Godret-Miertschin, Ryan Fleischmann, Vita Salsman, Sujith K. Joseph, and Nabil Ahmed. "Abstract 1151: CD6 isoforms improve CAR T cell fitness." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1151. http://dx.doi.org/10.1158/1538-7445.am2023-1151.
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Abstract The ability of chimeric antigen receptor (CAR) T cells to initiate and sustain an effective immune response entails a delicate balance between T-cell activation and deactivation and is key for complete tumor elimination. CD6 is a co-receptor that fine-tunes T cell receptor signal strength through a unique dual function intracellular domain. CD6 is alternatively spliced, creating isoforms that lack distinct regions which interact with activating or inhibitory adapter proteins, thereby delivering inhibitory or activating signals, respectively. We hypothesized that CAR T cell fitness, namely their ability to sustain their effector function, can be achieved by using alternatively spliced CD6 isoforms which lack exons responsible for inhibitory signaling. First, we discovered that overexpression of the canonical full-length CD6 molecule, isoform CD6A, resulted in marginal improvement of CAR T cell function, while its deletion using CRISPR/Cas9 depressed the antitumor CAR T cell functionality. This supported a net stimulatory role for CD6 in CAR T cell function. To study their effect on cellular fitness, we then synthesized and overexpressed known alternatively spliced cytoplasmic isoforms CD6B, CD6C, CD6D, CD6E, and CD6F on CAR T cells and, noted a significant tendency towards preserving the CAR T cell naïve and central memory compartments, upon tumor encounter. Overexpression of isoform CD6F, which lacks exon 9, and to a lesser extent isoforms CD6C and CD6E enhanced the short- and long-term cytotoxicity of HER2 and CD19 targeting CAR T cells when compared to CAR T cells alone or CAR T cells overexpressing, CD6A. Despite exhibiting a lower proliferation index, and lower CAR CD3ζ phosphorylation at rest, CD6F CAR T cells secreted significantly higher concentrations of the Th1 cytokine, IFN-γ, and mediated more sustained in vitro cytotoxicity long-term, with more complete elimination of large tumor cell loads. Lastly, in an orthotopic model of human glioblastoma, the adoptive transfer of CD6F HER2 CAR T cells induced a more significant but also more sustained anti-glioma effect that translated into a significant survival advantage for experimental animals. Our data support that the overexpression of the alternatively spliced CD6 isoforms improves CAR T cell fitness resulting in superior antitumor activity both in vitro and in vivo. Citation Format: Jessica S. Morris, Ahmed Z. Gad, Lea M. Godret-Miertschin, Ryan Fleischmann, Vita Salsman, Sujith K. Joseph, Nabil Ahmed. CD6 isoforms improve CAR T cell fitness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1151.
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Luksza, Marta. "Abstract IA11: Immune selection and predictability of cancer evolution." Cancer Immunology Research 10, no. 12_Supplement (December 1, 2022): IA11. http://dx.doi.org/10.1158/2326-6074.tumimm22-ia11.
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Abstract Immune editing of neoantigens is crucial for the success of immunotherapies, but it is still unknown to what extent the immune system naturally edits evolving tumors and what is the fitness cost associated with the presence of neoantigens. Here we develop a biophysically grounded neoantigen quality model, which quantifies the immunogenicity of tumor neoantigens. We use the model to define the fitness of tumor clones as a combination of negative selection due to immune recognition and positive selection due to oncogenic mutations. We investigate how pancreatic cancers – a lowly mutated, poorly immunogenic cancer, largely presumed to not be subject to immunoediting – evolve over 10 years. Our patient cohort includes a set of long-term survivors, who are characterized by high levels of immune infiltration of their primary tumors. With the fitness model, we show that long-term survivors evolve new clones of markedly lower immune fitness cost, to indicate clones with high-quality neoantigens are negatively selected. Importantly, the fitness model predicts the clonal composition of recurrent tumors of the patients. Thus, we submit longitudinal evidence that the human immune system naturally edits neoantigens. Furthermore, we present a model that describes how tumor cell populations evolve under immune pressure over time, with implications for cancer biology and therapy. Citation Format: Marta Luksza. Immune selection and predictability of cancer evolution [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr IA11.
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LeBleu, Valerie S. "Plasticity Enables Cooperation among Heterogeneous Cancer Cell Populations to Support Metastatic Fitness." Cancer Research 82, no. 10 (May 16, 2022): 1870–71. http://dx.doi.org/10.1158/0008-5472.can-22-0819.
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Abstract The invasive progression of cancer known as metastasis remains strongly associated with morbidity and lethality. New meaningful therapeutic interventions could be derived from a better understanding of the underlying processes driving cancer cell seeding and proliferation at secondary sites. Emerging findings regarding the heterogeneity of cancer cells observed in metastases have led us to revisit concepts surrounding metastatic fitness. Novel model systems to study the markers of cancer stem cell plasticity and their evolution during metastatic growth have uncovered that dynamic and heterogeneous cancer cell populations are observed during metastatic disease progression. Heinz and colleagues studied the heterogeneity of colorectal carcinomas, where primary tumors evolve alongside an epithelium well characterized for its self-renewing stem cell population. Their work revealed a functional dynamic interplay in the organization of the metastatic lesions as they transition from stagnating to expanding nodules, wherein the heterogeneous mixture of cancer cell stem cells with more differentiated cancer cells is essential for metastatic outgrowth. Their work supports that dynamic YAP signaling enables the growth-permissive heterogeneous composition of the metastatic nodule, in contrast with growth-restricted homogeneous compositions. See related article by Heinz et al., p. 1953
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Laruelle, Annick, Claudia Manini, José I. López, and André Rocha. "Early Evolution in Cancer: A Mathematical Support for Pathological and Genomic Evidence in Clear Cell Renal Cell Carcinoma." Cancers 15, no. 24 (December 18, 2023): 5897. http://dx.doi.org/10.3390/cancers15245897.
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Clear cell renal cell carcinoma (CCRCC) is an aggressive form of cancer and a paradigmatic example of intratumor heterogeneity (ITH). The hawk-dove game is a mathematical tool designed to analyze competition in biological systems. Using this game, the study reported here analyzes the early phase of CCRCC development, comparing clonal fitness in homogeneous (linear evolutionary) and highly heterogeneous (branching evolutionary) models. Fitness in the analysis is a measure of tumor aggressiveness. The results show that the fittest clone in a heterogeneous environment is fitter than the clone in a homogeneous context in the early phases of tumor evolution. Early and late periods of tumor evolution in CCRCC are also compared. The study shows the convergence of mathematical, histological, and genomics studies with respect to clonal aggressiveness in different periods of the natural history of CCRCC. Such convergence highlights the importance of multidisciplinary approaches for obtaining a better understanding of the intricacies of cancer.
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Singh, Balraj, Vanessa N. Sarli, and Anthony Lucci. "Abstract 47: A cell culture model of resistant cells in solid cancers that opportunistically switch between proliferation and quiescence." Cancer Research 83, no. 7_Supplement (April 4, 2023): 47. http://dx.doi.org/10.1158/1538-7445.am2023-47.
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Abstract Most cancer therapies inhibit proliferating cancer cells. A small subpopulation of cancer cells that survives by reversibly switching to quiescence, is often responsible for relapse/metastasis. Our goal is to model this resistant phenotype in cell culture, i.e., an ability to opportunistically switch between proliferation and quiescence. Cell culture models are convenient for mechanism-based manipulation and therapeutic evaluation. However, the major drawback is that typical cell culture conditions promote the proliferation of cancer cells irrespective of their fitness to survive in the body. To remedy this drawback, we have developed a strategy that eradicates majority (>99.99%) of cells in aggressive triple-negative breast cancer cell lines under a prolonged metabolic challenge (a lack of glutamine). Importantly, this selection protocol enriches highly adaptable rare cancer cells that survive in reversible quiescence. This function-based approach is good at modeling cell fitness in cell culture. Here we investigated whether the approach is generalizable to other solid cancers by evaluating two aggressive melanoma cell lines- a human melanoma cell line A375SM and a mouse melanoma cell line B16-BL6. We found that, similar to the results obtained with triple-negative breast cancer cell lines, a lack of glutamine in culture medium eradicated majority of cells in both melanoma cell lines. Rare melanoma cells persisted in quiescence and then proliferated indefinitely. To determine whether the surviving melanoma cells have characteristics of resistant cancer, we asked whether they are resistant to paclitaxel. We found that surviving melanoma cells, both A375SM-MA and B16-BL6-MA (MA for metabolic adaptability), are more resistant to paclitaxel than parental unselected cells. Our protocol to test paclitaxel resistance was optimized to assess whether the increased resistance was due to an ability of melanoma cells to survive in quiescence. The protocol involved treatment of melanoma cells with different concentrations of paclitaxel and then following surviving cells under a microscope for several weeks. After prolonged treatment with paclitaxel, we observed rare non-proliferating cells that would yield colonies upon removal of paclitaxel. In this manner, we found that both A375SM-MA and B16-BL6-MA cell lines had an increased ability to survive in quiescence while maintaining a robust ability to proliferate. We conclude that the function-based strategy presented here may be broadly applicable across resistant heterogeneous cancers for modeling a clinically relevant cancer cell phenotype in cell culture, i.e., an opportunistic switching between quiescence and proliferation. This model is suitable for evaluating therapies to overcome deep intrinsic resistance in cancer. Supported by a State of Texas Grant for Rare and Aggressive Cancers. Citation Format: Balraj Singh, Vanessa N. Sarli, Anthony Lucci. A cell culture model of resistant cells in solid cancers that opportunistically switch between proliferation and quiescence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 47.
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Gabbutt, Calum, and Trevor A. Graham. "Evolution’s cartographer: Mapping the fitness landscape in cancer." Cancer Cell 39, no. 10 (October 2021): 1311–13. http://dx.doi.org/10.1016/j.ccell.2021.09.002.
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Ladel, Luisa, Jessica Pham, Isabelle Oliver, Larisa Balaian, and Catriona HM Jamieson. "Abstract 3154: Assessing hematopoietic stem cell fitness within a nanobioreactor in microgravity." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3154. http://dx.doi.org/10.1158/1538-7445.am2022-3154.
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Abstract Microgravity coupled with increased radiation exposure aboard the ISS provides a unique environment to simulate and study response to injury, inflammatory signaling, aging, and (pre-)malignant transformation of normal human hematopoietic stem cells (HSCs) in an accelerated timeframe. The NASA Twins study suggests that genomic, epigenomic, epitranscriptomic, and proteomic changes may detrimentally impact hematopoietic stem and immune cell fitness and induce stem cell exhaustion (Garrett-Bakelman et al., Science, 2019). Moreover, changes indicative of pre-cancer stem cell generation such as increased chromosome translocations and inversions occurred and persisted post-flight. Additionally, a recent publication entitled Multisystem Toxicity in Cancer: Lessons from NASA’s Countermeasures Program found significant similarities between the multisystem physiological toxicities in cancer patients and during spaceflight (Scott et al, Cell 2019). These reports highlight the benefits of studying injury response, changes in mutational profiles and cancer evolution in microgravity at the stem cell level. For this study, we designed a novel bioreactor system to support the culture of donor-derived human HSCs in low Earth orbit (LEO). A sponge matrix and stromal cells model the microenvironment HSCs reside in within the bone marrow niche. Testing on Earth confirmed our system’s ability to maintain stem cell fitness over several weeks. To assess stem cell physiology in LEO over time, we lentivirally transduce a reporter into the HSCs pre-flight (Pineda et al., Scientific Reports 2016), which allows for cell cycle tracking via fluorescence imaging. This will provide data for assessment of stem cell health, maintenance and functionality. Furthermore, we will be analyzing mutational status post-flight, with a focus on signatures we have previously connected to (pre-)malignant transformation via RNA sequencing analysis (Jiang, Cancer Cell 2019). Our bioreactors are scheduled to launch as part of the SpaceX CRS-24 mission on Dec 21, 2021. This investigation may provide valuable insights into the maintenance of hematopoietic stem cell health and functionality, response to injury through accumulation of mutations and, eventually, the mechanisms fueling long-term (pre-)malignant transformation into leukemia stem cells. Citation Format: Luisa Ladel, Jessica Pham, Isabelle Oliver, Larisa Balaian, Catriona HM Jamieson. Assessing hematopoietic stem cell fitness within a nanobioreactor in microgravity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3154.
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Beck, Richard J., and Noemi Andor. "Abstract PR018: Adaptive local fitness landscapes for aneuploid karyotypes." Cancer Research 84, no. 3_Supplement_2 (February 1, 2024): PR018. http://dx.doi.org/10.1158/1538-7445.canevol23-pr018.
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Abstract Aneuploidy, which occurs in most solid tumors, dramatically alters the expression of many genes which in turn has broad phenotypic effects. Recent evidence suggests that specific aneuploid karyotypes confer a selective advantage. However, various questions remain unanswered regarding the magnitude of these selective advantages, as well as the repeatability and predictability of karyotype evolution. We developed ALFA-K (Adaptive Local Fitness landscapes for Aneuploid Karotypes) – the first approach to infer karyotype fitness landscapes in a context-dependent manner. Based on the dynamics of just a few subclones derived from longitudinal single cell sequencing data, our method can extrapolate the fitness of thousands of karyotypes. We validate the predictive power of our method on data from several P53 deficient cell lines which exhibited substantial subclonal evolution across multiple passages in vivo or in vitro. Based on topological analyses of the inferred fitness landscapes we investigated how mis-segregation rate itself shapes the stringency of karyotype evolution and whether karyotype evolution is subject to diminishing returns epistasis, sign epistasis or reciprocal sign epistasis. We adapted metrics from geo-statistics to study the fitness landscape of a P53 deficient 184-hTERT diploid breast epithelial cell line that underwent whole genome doubling (WGD) and found support for the hypothesis that WGD benefits tumor cells by enhancing their robustness against chromosomal instability. The stark phenotypic consequences of karyotype changes emphasize the value of predicting the evolutionary trajectory of karyotype composition when exposing cells to a new environment. Our work contributes to accumulating evidence that karyotype evolution is predictable. Citation Format: Richard J. Beck, Noemi Andor. Adaptive local fitness landscapes for aneuploid karyotypes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr PR018.
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Wang, Guoxiao, Pamela Swain, Ryan McGarrigle, and Natalia Romero. "Quality Assessment of Metabolic Fitness during T Cell and NK Cell Expansion." Journal of Immunology 212, no. 1_Supplement (May 1, 2024): 0930_5513. http://dx.doi.org/10.4049/jimmunol.212.supp.0930.5513.
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Abstract CAR-T cells have revolutionized cancer treatment, and other cell types like CAR-NK cells are also showing promising results. Engineered cells generally need to be expanded ex vivo before being transfused into patients. Growth conditions, including expansion platform, cell culture media, and cytokine composition, time of expansion, etc., can have a strong effect on the characteristics of the final products and need to be monitored to establish the appropriate development process. Recent developments highlight the significance of cell metabolism in influencing immune responses and the anti-tumor efficacy of cell therapies. In the present study, we utilized Seahorse XF technology and assays to characterize T cell and NK cell metabolic fitness during cell expansion. We cultured human T cells and NK cells under different expansion conditions including culture media, culture devices, and cytokine combinations, and sampled cells at different time points for quality assessment of metabolic fitness. Using the new Seahorse XF assay alongside immunophenotypic characterization using Novocyte Flow Cytometry, we obtained robust information on mitochondrial and glycolytic energy production, metabolic poise, and the bioenergetic capacity of the expanded cells, allowing us to identify conditions that resulted in increased metabolic fitness of the cell population that can contribute to defining cell expansion conditions during immunotherapy development.
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Thakur, Shefali, Vincent Cahais, Tereza Turkova, Tomas Zikmund, Claire Renard, Tomáš Stopka, Michael Korenjak, and Jiri Zavadil. "Chromatin Remodeler Smarca5 Is Required for Cancer-Related Processes of Primary Cell Fitness and Immortalization." Cells 11, no. 5 (February 25, 2022): 808. http://dx.doi.org/10.3390/cells11050808.
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Smarca5, an ATPase of the ISWI class of chromatin remodelers, is a key regulator of chromatin structure, cell cycle and DNA repair. Smarca5 is deregulated in leukemia and breast, lung and gastric cancers. However, its role in oncogenesis is not well understood. Chromatin remodelers often play dosage-dependent roles in cancer. We therefore investigated the epigenomic and phenotypic impact of controlled stepwise attenuation of Smarca5 function in the context of primary cell transformation, a process relevant to tumor formation. Upon conditional single- or double-allele Smarca5 deletion, the cells underwent both accelerated growth arrest and senescence entry and displayed gradually increased sensitivity to genotoxic insults. These phenotypic characteristics were explained by specific remodeling of the chromatin structure and the transcriptome in primary cells prior to the immortalization onset. These molecular programs implicated Smarca5 requirement in DNA damage repair, telomere maintenance, cell cycle progression and in restricting apoptosis and cellular senescence. Consistent with the molecular programs, we demonstrate for the first time that Smarca5-deficient primary cells exhibit dramatically decreased capacity to bypass senescence and immortalize, an indispensable step during cell transformation and cancer development. Thus, Smarca5 plays a crucial role in key homeostatic processes and sustains cancer-promoting molecular programs and cellular phenotypes.
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Rivadeneira, Dayana B., and Greg M. Delgoffe. "Antitumor T-cell Reconditioning: Improving Metabolic Fitness for Optimal Cancer Immunotherapy." Clinical Cancer Research 24, no. 11 (January 31, 2018): 2473–81. http://dx.doi.org/10.1158/1078-0432.ccr-17-0894.
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Clemente-Suárez, Vicente Javier, Alexandra Martín-Rodríguez, Laura Redondo-Flórez, Pablo Ruisoto, Eduardo Navarro-Jiménez, Domingo Jesús Ramos-Campo, and José Francisco Tornero-Aguilera. "Metabolic Health, Mitochondrial Fitness, Physical Activity, and Cancer." Cancers 15, no. 3 (January 28, 2023): 814. http://dx.doi.org/10.3390/cancers15030814.
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Cancer continues to be a significant global health issue. Traditional genetic-based approaches to understanding and treating cancer have had limited success. Researchers are increasingly exploring the impact of the environment, specifically inflammation and metabolism, on cancer development. Examining the role of mitochondria in this context is crucial for understanding the connections between metabolic health, physical activity, and cancer. This study aimed to review the literature on this topic through a comprehensive narrative review of various databases including MedLine (PubMed), Cochrane (Wiley), Embase, PsychINFO, and CinAhl. The review highlighted the importance of mitochondrial function in overall health and in regulating key events in cancer development, such as apoptosis. The concept of “mitochondrial fitness” emphasizes the crucial role of mitochondria in cell metabolism, particularly their oxidative functions, and how proper function can prevent replication errors and regulate apoptosis. Engaging in high-energy-demanding movement, such as exercise, is a powerful intervention for improving mitochondrial function and increasing resistance to environmental stressors. These findings support the significance of considering the role of the environment, specifically inflammation and metabolism, in cancer development and treatment. Further research is required to fully understand the mechanisms by which physical activity improves mitochondrial function and potentially reduces the risk of cancer.
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Paul, Aswathy Mary, Revikumar Amjesh, Bijesh George, Deivendran Sankaran, Oleta A. Sandiford, Pranela Rameshwar, Madhavan Radhakrishna Pillai, and Rakesh Kumar. "The Revelation of Continuously Organized, Co-Overexpressed Protein-Coding Genes with Roles in Cellular Communications in Breast Cancer." Cells 11, no. 23 (November 28, 2022): 3806. http://dx.doi.org/10.3390/cells11233806.
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Many human cancers, including breast cancer, are polygenic and involve the co-dysregulation of multiple regulatory molecules and pathways. Though the overexpression of genes and amplified chromosomal regions have been closely linked in breast cancer, the notion of the co-upregulation of genes at a single locus remains poorly described. Here, we describe the co-overexpression of 34 continuously organized protein-coding genes with diverse functions at 8q.24.3(143437655-144326919) in breast and other cancer types, the CanCord34 genes. In total, 10 out of 34 genes have not been reported to be overexpressed in breast cancer. Interestingly, the overexpression of CanCord34 genes is not necessarily associated with genomic amplification and is independent of hormonal or HER2 status in breast cancer. CanCord34 genes exhibit diverse known and predicted functions, including enzymatic activities, cell viability, multipotency, cancer stem cells, and secretory activities, including extracellular vesicles. The co-overexpression of 33 of the CanCord34 genes in a multivariant analysis was correlated with poor survival among patients with breast cancer. The analysis of the genome-wide RNAi functional screening, cell dependency fitness, and breast cancer stem cell databases indicated that three diverse overexpressed CanCord34 genes, including a component of spliceosome PUF60, a component of exosome complex EXOSC4, and a ribosomal biogenesis factor BOP1, shared roles in cell viability, cell fitness, and stem cell phenotypes. In addition, 17 of the CanCord34 genes were found in the microvesicles (MVs) secreted from the mesenchymal stem cells that were primed with MDA-MB-231 breast cancer cells. Since these MVs were important in the chemoresistance and dedifferentiation of breast cancer cells into cancer stem cells, these findings highlight the significance of the CanCord34 genes in cellular communications. In brief, the persistent co-overexpression of CanCord34 genes with diverse functions can lead to the dysregulation of complementary functions in breast cancer. In brief, the present study provides new insights into the polygenic nature of breast cancer and opens new research avenues for basic, preclinical, and therapeutic studies in human cancer.
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Qazi, Maleeha, Sabra Salim, Kevin R. Brown, Neil Savage, Nicholas Mickolajewicz, Hong Han, Chirayu R. Chokshi, et al. "TMOD-15. CHARACTERIZATION OF THE MINIMAL RESIDUAL DISEASE STATE REVEALS DISTINCT EVOLUTIONARY TRAJECTORIES OF HUMAN GLIOBLASTOMA." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi218. http://dx.doi.org/10.1093/neuonc/noab196.876.
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Abstract Recurrence of solid tumors renders patients vulnerable to a distinctly advanced, highly treatment-refractory disease state that has an increased mutational burden and novel oncogenic drivers not detected at initial diagnosis. Improving outcomes for recurrent cancers requires a better understanding of cancer cell populations that expand from the post-therapy, minimal residual disease (MRD) state. We profiled barcoded tumor cell populations through therapy at tumor initiation/engraftment, MRD and recurrence in our therapy-adapted, patient-derived xenograft models of glioblastoma (GBM). Tumors showed distinct patterns of recurrence in which clonal populations exhibited either a priori, pre-existing fitness, or equipotent fitness acquired through therapy. Characterization of the MRD state by single-cell and bulk RNA sequencing revealed a tumor-intrinsic immunomodulatory signature with strong prognostic significance at the transcriptomic level and in proteomic analysis of cerebrospinal fluid (CSF) collected from GBM patients at all stages of disease. Our results provide insight into the innate and therapy-driven dynamics of human glioblastoma, and the prognostic value of the interrogating of the MRD state in solid cancers.
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Chen, Jin. "HIF1α or HIF2α: Enhancing CD8+ T-cell Fitness for Antitumor Immunity." Cancer Immunology Research 9, no. 4 (April 2021): 364. http://dx.doi.org/10.1158/2326-6066.cir-21-0114.
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Conti, Michelle M., Julie M. Ghizzoni, Ana Gil-Bona, Wen Wang, Michael Costanzo, Rui Li, Mackenzie J. Flynn, et al. "Repression of essential cell cycle genes increases cellular fitness." PLOS Genetics 18, no. 8 (August 29, 2022): e1010349. http://dx.doi.org/10.1371/journal.pgen.1010349.
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A network of transcription factors (TFs) coordinates transcription with cell cycle events in eukaryotes. Most TFs in the network are phosphorylated by cyclin-dependent kinase (CDK), which limits their activities during the cell cycle. Here, we investigate the physiological consequences of disrupting CDK regulation of the paralogous repressors Yhp1 and Yox1 in yeast. Blocking Yhp1/Yox1 phosphorylation increases their levels and decreases expression of essential cell cycle regulatory genes which, unexpectedly, increases cellular fitness in optimal growth conditions. Using synthetic genetic interaction screens, we find that Yhp1/Yox1 mutations improve the fitness of mutants with mitotic defects, including condensin mutants. Blocking Yhp1/Yox1 phosphorylation simultaneously accelerates the G1/S transition and delays mitotic exit, without decreasing proliferation rate. This mitotic delay partially reverses the chromosome segregation defect of condensin mutants, potentially explaining their increased fitness when combined with Yhp1/Yox1 phosphomutants. These findings reveal how altering expression of cell cycle genes leads to a redistribution of cell cycle timing and confers a fitness advantage to cells.
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Di Gregorio, Aida, Sarah Bowling, and Tristan Argeo Rodriguez. "Cell Competition and Its Role in the Regulation of Cell Fitness from Development to Cancer." Developmental Cell 38, no. 6 (September 2016): 621–34. http://dx.doi.org/10.1016/j.devcel.2016.08.012.
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Kuzuoglu-Ozturk, Duygu, Zhiqiang Hu, Martina Rama, Emily Devericks, Jacob Weiss, Gary G. Chiang, Stephen T. Worland, et al. "Revealing molecular pathways for cancer cell fitness through a genetic screen of the cancer translatome." Cell Reports 35, no. 13 (June 2021): 109321. http://dx.doi.org/10.1016/j.celrep.2021.109321.
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Aparicio, Samuel. "Abstract IA15: Single cell origins and targeting of genomic instability in breast cancers." Cancer Research 84, no. 3_Supplement_1 (February 1, 2024): IA15. http://dx.doi.org/10.1158/1538-7445.advbc23-ia15.
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Abstract Early whole genome sequencing studies have emphasised the different modes by which breast cancers can evolve. However, bulk NGS tissue analysis obscures mutations that are contemporaneous and/or lead to negative selection, and does not resolve clone specific metrics such as replication rate and fitness. We have developed single cell genome sequencing methods (Laks et al., Cell 2019) to identify large scale copy number-structural (CNA-SV) mutational processes that result in genomic shuffling through the duplication or deletion of chromosomal regions, obscured by bulk tissue analysis. This has revealed the existence and activity of distinct “foreground” mutational processes, i.e. mutational events in single mitoses that are observed directly, before the effects of purifying selection. We discovered that foreground processes are preferentially associated with background patterns of genome instability (Funnell et al., Nature 2022). We also discovered that CNA-SV mutational patterns are associated with relative sensitivity or resistance to platinum, a commonly used DNA targeting agent in TNBC and HGSOC. Our second recent discovery has been the association of CNA-SV mutations with clonal resistance to platinum in TNBC (Salehi et al., Nature 2021). Taken together, we now understand that ongoing CNA-SV mutations contribute to the evolution of fitness landscapes for DNA targeting therapeutics. In parallel work (Xu et al Nat. comms 2017) we have discovered stabilisers of folded DNA guanine stacked bases, G-quadruplexes (G4), to be synthetically lethal in contexts including HR and TMEJ that are underpinned by the single cell processes identified through single genome sequencing. To this end we have recently observed G4-ligand clinical activity in BRCA2 and PALB2 mutated cancers in a phase 1 trial (Hilton et al, Nature communication 2022). Citation Format: Samuel Aparicio. Single cell origins and targeting of genomic instability in breast cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr IA15.
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Salehi, Sohrab, Farhia Kabeer, Nicholas Ceglia, Mirela Andronescu, Marc J. Williams, Kieran R. Campbell, Tehmina Masud, et al. "Clonal fitness inferred from time-series modelling of single-cell cancer genomes." Nature 595, no. 7868 (June 23, 2021): 585–90. http://dx.doi.org/10.1038/s41586-021-03648-3.
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Quick, Kelly, and Carolyn A. Dennehy. "Natural Killer Cell Cytolytic Activity and Fitness Status in Breast Cancer Patients." Medicine & Science in Sports & Exercise 36, Supplement (May 2004): S285. http://dx.doi.org/10.1249/00005768-200405001-01368.
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Quick, Kelly, and Carolyn A. Dennehy. "Natural Killer Cell Cytolytic Activity and Fitness Status in Breast Cancer Patients." Medicine & Science in Sports & Exercise 36, Supplement (May 2004): S285. http://dx.doi.org/10.1097/00005768-200405001-01368.
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Vendramin, Roberto, Yvessa Verheyden, Hideaki Ishikawa, Lucas Goedert, Emilien Nicolas, Kritika Saraf, Alexandros Armaos, et al. "SAMMSON fosters cancer cell fitness by concertedly enhancing mitochondrial and cytosolic translation." Nature Structural & Molecular Biology 25, no. 11 (October 29, 2018): 1035–46. http://dx.doi.org/10.1038/s41594-018-0143-4.
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Hollern, Daniel. "Memory B cell fitness and anergy has significant links to cancer lethality." Cell 187, no. 17 (August 2024): 4551–53. http://dx.doi.org/10.1016/j.cell.2024.07.037.
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Krishnamoorthy, Gnana P., Anthony Glover, Brian Untch, Mahesh Saqcena, Dina Vukel, Katherine Berman, Omar Abdel-Wahab, Robert K. Bradley, Jeffrey A. Knauf, and James A. Fagin. "Abstract 986: RBM10 loss in thyroid cancer leads to aberrant splicing of cytoskeletal and extracellular matrix mRNAs and increased metastatic fitness." Cancer Research 82, no. 12_Supplement (June 15, 2022): 986. http://dx.doi.org/10.1158/1538-7445.am2022-986.
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Abstract NGS studies implicate dysregulation of the splicing machinery in the development of diverse cancers. The X-chromosome RBM10 gene encodes an RNA-binding protein that modulates transcriptome-wide cassette exon splicing. Truncation and missense RBM10 mutations are enriched (11%) in non-anaplastic thyroid cancers of patients who died of metastatic disease. MSK-MET, an integrated pan-cancer cohort of tumor genomic and clinical outcome data showed RBM10 alterations associate with metastatic burden in thyroid cancer. Within the MSK-IMPACT thyroid cancer cohort, 44% of RBM10 alterations co-occur with RAS mutations. We developed a murine Rbm10 floxed allele, which results in a non-functional transcript. Thyroid-specific Rbm10 inactivation through Tpo-Cre did not induce a phenotype. When crossed with FR-HrasG12V mice, which upon recombination generate endogenous expression of HrasG12V, Hras/Rbm10 mice developed thyroid cancers, ~ 20% of which were metastatic to lung. Cell lines derived from these tumors showed high penetrance of lung metastases after tail vein or orthotopic implantation into the thyroid. We identified splicing targets of RBM10 by high depth RNAseq of 5 isogenic human thyroid cancer cell lines (2 RBM10-null with dox-induced RBM10; 3 RBM10 WT with RBM10 shRNA). The common abnormalities associated with RBM10 loss were exon inclusion events. Ingenuity Pathway Analysis of global transcriptomes in RBM10 isogenic human thyroid cancer cell lines showed enrichment in pro-migratory, aberrant integrin and RHO/RAC signaling expression signatures. Enriched GO analysis confined to genes subject to aberrant splicing by RBM10 loss extended these findings, with the top terms being cell adhesion, cytoskeleton, cadherin and integrin binding. RBM10 loss was associated with increased cell migration velocity in vitro as measured by time lapse imaging. Key cytoskeletal and extracellular matrix genes subject to exon inclusion events included vinculin (VCL), tenascin C (TNC), CD44, fibronectin (FN1) and tropomyosin 1 (TPM1). Isoform-specific knockdown of the VCL splice inclusion cassette exon that leads to illegitimate expression of metavinculin (mVCL) reduced cell migration, whereas isoform-specific knockdown of TNC and CD44 exon inclusion events reduced cell invasiveness in vitro. Rho GTPases transduce signals from the ECM to integrin receptors to regulate cell adhesion, migration, and invasiveness. Consistent with this, RBM10 overexpression in RBM10 null cells reduced RAC1-GTP levels. Finally, RBM10 re-expression in RBM10 null cells reversed metastatic competency in vivo. In conclusion, RBM10 loss alters the ratio of cassette exon inclusion events in a subset of transcripts that regulate interactions between the ECM and the cytoskeleton, leading to RHO/RAC activation and governing a process favoring increased cell movement and metastatic competence. Citation Format: Gnana P. Krishnamoorthy, Anthony Glover, Brian Untch, Mahesh Saqcena, Dina Vukel, Katherine Berman, Omar Abdel-Wahab, Robert K. Bradley, Jeffrey A. Knauf, James A. Fagin. RBM10 loss in thyroid cancer leads to aberrant splicing of cytoskeletal and extracellular matrix mRNAs and increased metastatic fitness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 986.
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Marozas, Ian, Zhiyang Zeng, Mike Valley, Jolanta Vidugiriene, James Cali, and Wenhui Zhou. "Abstract 4844: Development of an oxygen consumption rate assay for a standard plate reader." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4844. http://dx.doi.org/10.1158/1538-7445.am2023-4844.
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Abstract Cells generate ATP by two metabolic pathways, oxidative phosphorylation (OXPHOS) and glycolysis. Together, the amount of ATP generated by both OXPHOS and glycolysis define a cell’s metabolic phenotype and fitness. Researchers are interested in methods to characterize cellular metabolic fitness, which can be a powerful a selection criterion for cell-based therapies such as CAR-T cell therapy. Researchers are also interested in measuring the effects of drug treatment on metabolic fitness, to identify metabolic targets for cancer therapeutics and to determine mitochondrial toxicity of novel therapeutics. Here, we have developed a low-cost strategy for a standard plate reader to monitor the rate change of oxygen concentration, or the oxygen consumption rate (OCR), which is a measure of OXPHOS activity. In our assay, oxygen quenches a phosphorescent porphyrin dye in a concentration dependent manner, allowing one to calculate the oxygen concentration of the culture system with the Stern-Volmer relationship. The porphyrin dye is embedded within nanobeads that are suspended above the cell monolayer and the phosphorescence of the beads is measured from the bottom of the well with a standard plate reader. We found that the OCR increased with cell seeding density in three separate cell lines: HEP-G2, HCT-116, and K-562 suspension cells. We showed that inhibitors of the electron transport chain (ETC) decreased OCR, whereas an uncoupler of the electron transport chain, FCCP, increased OCR in a dose dependent manner. Lastly, mitochondrial fitness (e.g., spare respiratory capacity) was determined by sequentially dosing the mitochondria with poisons specific to the different ETC complexes. Citation Format: Ian Marozas, Zhiyang Zeng, Mike Valley, Jolanta Vidugiriene, James Cali, Wenhui Zhou. Development of an oxygen consumption rate assay for a standard plate reader. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4844.
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Coggan, Helena M. K., Carlos Martínez-Ruiz, James R. M. Black, Kristiana Grigoriadis, Nicholas McGranahan, and Jasmin Fisher. "Abstract PR013: An agent-based modelling framework to study cell plasticity in non-small cell lung cancer." Cancer Research 84, no. 3_Supplement_2 (February 1, 2024): PR013. http://dx.doi.org/10.1158/1538-7445.canevol23-pr013.
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Abstract Recent breakthroughs in phylogenetic analysis of bulk tissue have allowed researchers to reconstruct the evolutionary histories of tumours. The hope is that knowledge of the order and timing of genetic mutations will allow us to characterise the properties of early-stage cancer cells, to better identify and target them. This is complicated by the phenomenon of tumour plasticity, the ability of cells to acquire the hallmarks of cancer via mechanisms other than heritable genetic mutation. In a tumour with only genetic heritability, changes in cell phenotype would occur only as a result of genetic mutations. By contrast, non-genetic heritability could lead to a disconnect between genotype and phenotype. Whilst both mechanisms are likely to impact on cancer development, we ask whether one has a significantly stronger influence than the other by simulating tumour growth under each regime and comparing the distribution of mutations obtained in either case to patient data. Here, we address this question in a real patient cohort by adapting a mathematical model of lung tumour evolution, which we use to test the validity of two scenarios. In a ‘low-plasticity’ scenario, changes to reproductive fitness occur when cells acquire mutations in the exome. Mutations may be ‘drivers’ (beneficial) or ‘passengers’ (deleterious or neutral). In a ‘high-plasticity’ scenario, mutations have no effect on cell fitness. Cells experience ‘driver-like’ or ‘passenger-like’ cell fitness changes on division, without leaving a genetic mark. The model describes three-dimensional growth of a tumour from a single cell and incorporates biologically-informed death patterns and local competition for space and resources. When the simulation has reached a realistic size, cells on the surface are sampled and sequenced to predict the relatedness of mutations present at detectable frequencies in each of several regions. The outputs are designed to allow comparison with those of the TRACERx cohort of 421 non-small- cell lung cancer patients (NSCLC), comprising multi-region whole-exome (WXS) and bulk RNA sequencing. In this ongoing work, we show results from a large cohort of simulations under both scenarios and predict corresponding patterns of genetic similarity. This allows us to use approximate Bayesian computation (ABC) to predict the mechanisms at play in the TRACERx cohort of 421 non-small-cell lung cancer patients (NSCLC). We present a novel ‘meta-inference’ approach, where evolutionary parameters are fit to each patient’s data using well-chosen summary statistics. Given the size of the TRACERx cohort, this enables the evaluation of each scenario by examining the plausibility and similarity of output parameters obtained across patients. We hope that this work will shed light on the role of heritability in lung cancer development and guide future research into therapeutic approaches. Citation Format: Helena M. K. Coggan, Carlos Martínez-Ruiz, James R. M. Black, Kristiana Grigoriadis, Nicholas McGranahan, Jasmin Fisher. An agent-based modelling framework to study cell plasticity in non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr PR013.
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Sridhar, Rajagopalan, Vernon Bond, Jacquelyn Dunmore-Griffith, Valerie M. Cousins, Renshu Zhang, and Richard M. Millis. "Relationship Between Aerobic Fitness, the Serum IGF-1 Profiles of Healthy Young Adult African American Males, and Growth of Prostate Cancer Cells." American Journal of Men's Health 11, no. 1 (June 22, 2016): 92–98. http://dx.doi.org/10.1177/1557988315587740.
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The growth of prostate tumors is mediated by the bioavailability of androgens and insulin-like growth factors. This study tested the hypothesis that healthy young adult African American men exhibiting low aerobic capacity (fitness) have serum insulin-like growth Factor-1 (IGF-1) and testosterone levels that promote growth of prostate cancer cells. A cross-sectional data research design was used to study groups of 18- to 26-year-old healthy men exhibiting low and moderate aerobic fitness, based on their peak oxygen consumption (VO2peak). The individual serum levels of IGF-1, IGF-1 binding protein-3 (IGFBP-3), and testosterone were measured. In vitro growth of androgen-dependent LNCaP prostate tumor cells was measured after incubation in culture medium fortified with each subject’s serum. Aerobic capacity was significantly greater in the moderate-fitness group than in the low-fitness group without an intergroup difference in body mass index. The serum IGF-1 concentration was significantly higher in the low-fitness group in the absence of an intergroup difference in serum testosterone. The serum IGFBP-3 concentration was significantly lower in the low-fitness group. Prostate tumor cell growth was significantly greater in the cultures incubated in media containing the sera of the low-fitness group than in the sera of the moderate-fitness group. These findings suggest that moderate aerobic fitness in young adults may decrease the circulating levels of free IGF-1 and lower the potential to support growth of prostate cancer cells.