Статті в журналах: "Luminal lineage"

1

Matsuo, Junichi, Naing Naing Mon, Daisuke Douchi, Akihiro Yamamura, Madhura Kulkarni, Dede Liana Heng, Sabirah Chen, et al. "A Runx1-enhancer Element eR1 Identified Lineage Restricted Mammary Luminal Stem Cells." Stem Cells 40, no. 1 (January 1, 2022): 112–22. http://dx.doi.org/10.1093/stmcls/sxab009.

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Abstract Mammary gland homeostasis is maintained by adult tissue stem-progenitor cells residing within the luminal and basal epithelia. Dysregulation of mammary stem cells is a key mechanism for cancer development. However, stem cell characterization is challenging because reporter models using cell-specific promoters do not fully recapitulate the mammary stem cell populations. We previously found that a 270-basepair Runx1 enhancer element, named eR1, marked stem cells in the blood and stomach. Here, we identified eR1 activity in a rare subpopulation of the ERα-negative luminal epithelium in mouse mammary glands. Lineage-tracing using an eR1-CreERT2 mouse model revealed that eR1+ luminal cells generated the entire luminal lineage and milk-secreting alveoli—eR1 therefore specifically marks lineage-restricted luminal stem cells. eR1-targeted-conditional knockout of Runx1 led to the expansion of luminal epithelial cells, accompanied by elevated ERα expression. Our findings demonstrate a definitive role for Runx1 in the regulation of the eR1-positive luminal stem cell proliferation during mammary homeostasis. Our findings identify a mechanistic link for Runx1 in stem cell proliferation and its dysregulation in breast cancer. Runx1 inactivation is therefore likely to be an early hit in the cell-of-origin of ERα+ luminal type breast cancer.

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2

Miyano, Masaru, Rosalyn W. Sayaman, Parijat Senapati, Stefan Hinz, Victoria E. Seewaldt, Dustin Schones, and Mark A. LaBarge. "Abstract PR006: Integrating noise into a signal: Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility." Cancer Research 83, no. 2_Supplement_1 (January 15, 2023): PR006. http://dx.doi.org/10.1158/1538-7445.agca22-pr006.

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Abstract Effects from aging in any single cell are unpredictable, whereas aging phenotypes at the organ and tissue levels tend to appear as stereotypical changes. The mammary epithelium, the origin of breast carcinomas, is a bilayer of two major phenotypically and functionally distinct cell lineages, the luminal epithelial and myoepithelial cells. We have shown that luminal epithelia exhibit substantial stereotypical changes with age, which merits attention as they are putative breast cancer cells of origin. Hallmark aging changes in mammary gland are loss of lineage specificity in luminal epithelia exemplified by acquiring expression of proteins normally reserved for myoepithelial cells, and progenitor cells that accumulate and attain a basal differentiation bias. We hypothesize that effects from aging that impinge upon maintenance of lineage specificity increases susceptibility to cancer initiation. Indeed, histologically normal breast tissue from young women, who were known to be highly susceptible to breast cancer because they harbor a germline mutation in BRCA1, BRCA2, or PALB2 genes, exhibited hallmarks of accelerated aging. These included increased proportions of luminal epithelial cells with acquired myoepithelial proteins, acceleration of a breast specific biological clock by 10 to 40 years compared to chronological age, and a basal differentiation bias or failure of differentiation of cKit+ progenitors. To gain insight into the underlying molecular changes we interrogated transcriptomes, proteomes, and methylomes of mammary epithelia at lineage resolution. Strikingly, age-dependent differential gene expression and DNA methylation occurred almost exclusively in luminal epithelia, whereas changes due to increased variance of gene and protein expression occurs in both luminal and myoepithelial lineages. Most gene changes that were previously associated with early breast cancer are detectable as age-driven changes in normal luminal epithelia. The genes with age-dependent differential and variant changes in expression distinguish normal tissue from breast cancers and are predictive of PAM50 breast cancer subtypes. Heterochronus, multilineage, co-cultures demonstrated that the age-dependent phenotype of luminal cells is at least partly dependent on the microenvironment created on the apical surfaces of neighboring myoepithelial cells. We show that increased variance is a substantial outcome of aging and is likely central to understanding increased susceptibility to breast cancer with age. We speculate that the luminal epithelium is a site of integration of the variant responses to aging in their surrounding tissue, and that their emergent phenotype of aging both endows cells with the ability to become a cancer cell of origin and embodies a biosensor that presages one’s cancer susceptibility. Citation Format: Masaru Miyano, Rosalyn W. Sayaman, Parijat Senapati, Stefan Hinz, Victoria E. Seewaldt, Dustin Schones, Mark A. LaBarge. Integrating noise into a signal: Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR006.

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3

Feng, Felix Yi-Chung, Shuang Zhao, Seiwon Laura Chang, Nicholas Erho, Jonathan Lehrer, Mohammed Alshalalfa, Matthew R. Cooperberg, et al. "Luminal and basal subtyping of prostate cancer." Journal of Clinical Oncology 35, no. 6_suppl (February 20, 2017): 3. http://dx.doi.org/10.1200/jco.2017.35.6_suppl.3.

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3 Background: There is a clear need to develop a clinically relevant molecular subtyping approach for prostate cancer. We hypothesized that prostate cancer can be subtyped based on luminal versus basal lineage. Methods: We applied the PAM50 classifier, which is used clinically to identify luminal and basal cancers in breast cancer, to subtype a total of 3,782 prostate cancer samples using a high-density microarray platform run in a CLIA-certified laboratory. We examined the associations of these subtypes and clinical outcomes. Results: We demonstrate that PAM50 segregates prostate cancer into three reproducible subtypes in both retrospective cohorts and on prospective validation: luminal A (33.3%-34.3%), luminal B (28.5%-32.6%), and basal (34.1%-37.1%). Luminal B prostate cancers exhibited the worst clinical prognoses, followed by basal and luminal A subtypes (10-year biochemical recurrence-free survival: 29/39/41%; distant metastasis-free survival: 53/73/73%; prostate cancer-specific survival: 78/86/89%; overall survival: 69/80/82% respectively) on both univariable and multivariable analyses accounting for standard clinicopathologic prognostic factors. Known luminal lineage markers, such as NKX3.1 and KRT18, and the basal lineage CD49f signature, were enriched in luminal- and basal-like cancers respectively, demonstrating the connection between these subtypes and established prostate cancer biology. While both luminal-like subtypes were associated with increased AR expression and signaling, only luminal B prostate cancers were significantly associated with post-operative response to androgen deprivation therapy (ADT) in a subset analysis matching patients based on clinicopathologic variables (interaction p = 0.006, luminal B 10-year metastasis: 33% (treated) vs. 55% (untreated), non-luminal B: 37% (treated) vs. 21% (untreated)). Conclusions: These findings contribute novel insight into the biology of prostate cancer, and provide translatable clinical tools for personalizing post-operative ADT for patients with prostate cancer. Similar to breast cancer, these findings suggest that luminal/basal subtyping may be useful in treatment selection in prostate cancer.

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4

Wang, Chunhui, John R. Christin, Maja H. Oktay, and Wenjun Guo. "Lineage-Biased Stem Cells Maintain Estrogen-Receptor-Positive and -Negative Mouse Mammary Luminal Lineages." Cell Reports 18, no. 12 (March 2017): 2825–35. http://dx.doi.org/10.1016/j.celrep.2017.02.071.

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5

Yoo, Kyung Hyun, Sumin Oh, Keunsoo Kang, Chaochen Wang, Gertraud W. Robinson, Kai Ge, and Lothar Hennighausen. "Histone Demethylase KDM6A Controls the Mammary Luminal Lineage through Enzyme-Independent Mechanisms." Molecular and Cellular Biology 36, no. 16 (May 23, 2016): 2108–20. http://dx.doi.org/10.1128/mcb.00089-16.

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Establishment of the mammary luminal cell lineage is controlled primarily by hormones and through specific transcription factors (TFs). Previous studies have linked histone methyltransferases to the differentiation of mammary epithelium, thus opening the possibility of biological significance of counteracting demethylases. We have now demonstrated an essential role for the H3K27me3 demethylase KDM6A in generating a balanced alveolar compartment. Deletion ofKdm6ain the mammary luminal cell lineage led to a paucity of luminal cells and an excessive expansion of basal cells, bothin vivoandin vitro. The inability to form structurally normal ducts and alveoli during pregnancy resulted in lactation failure. Mutant luminal cells did not exhibit their distinctive transcription factor pattern and displayed basal characteristics. The genomic H3K27me3 landscape was unaltered in mutant tissue, and support for a demethylase-independent mechanism came from mice expressing a catalytically inactive KDM6A. Mammary tissue developed normally in these mice. Chromatin immunoprecipitation sequencing (ChIP-seq) experiments demonstrated KDM6A binding to putative enhancers enriched for key mammary TFs and H3K27ac. This study demonstrated for the first time that the mammary luminal lineage relies on KDM6A to ensure a transcription program leading to differentiated alveoli. Failure to fully implement this program results in structurally and functionally impaired mammary tissue.

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6

Shalabi, Sundus F., Masaru Miyano, Rosalyn W. Sayaman, Jennifer C. Lopez, Tiina A. Jokela, Michael E. Todhunter, Stefan Hinz, et al. "Evidence for accelerated aging in mammary epithelia of women carrying germline BRCA1 or BRCA2 mutations." Nature Aging 1, no. 9 (September 2021): 838–49. http://dx.doi.org/10.1038/s43587-021-00104-9.

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AbstractDuring aging in the human mammary gland, luminal epithelial cells lose lineage fidelity by expressing markers normally expressed in myoepithelial cells. We hypothesize that loss of lineage fidelity is a general manifestation of epithelia that are susceptible to cancer initiation. In the present study, we show that histologically normal breast tissue from younger women who are susceptible to breast cancer, as a result of harboring a germline mutation in BRCA1, BRCA2 or PALB2 genes, exhibits hallmarks of accelerated aging. These include proportionately increased luminal epithelial cells that acquired myoepithelial markers, decreased proportions of myoepithelial cells and a basal differentiation bias or failure of differentiation of cKit+ progenitors. High-risk luminal and myoepithelial cells are transcriptionally enriched for genes of the opposite lineage, inflammatory- and cancer-related pathways. We have identified breast-aging hallmarks that reflect a convergent biology of cancer susceptibility, regardless of the specific underlying genetic or age-dependent risk or the associated breast cancer subtype.

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7

Miyano, Masaru, Sundus Shalabi, Rosalyn W. Sayaman, Martha Stampfer, Victoria E. Seewaldt, and Mark A. LaBarge. "Abstract 5682: Accelerated biological age is a driver of cancer susceptibility in genetic high risk breast tissue." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5682. http://dx.doi.org/10.1158/1538-7445.am2022-5682.

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Abstract During aging in the human mammary gland, luminal epithelial cells lose lineage fidelity by expressing markers normally expressed in myoepithelial cells. We hypothesize that loss of lineage fidelity is a general manifestation of epithelia that are susceptible to cancer initiation. We show that histologically normal breast tissue from younger women who are susceptible to breast cancer because they harbor a germline mutation in BRCA1, BRCA2, or PALB2 genes, exhibit hallmarks of accelerated aging. These include proportionately increased luminal epithelial cells that acquired myoepithelial markers, decreased proportions of myoepithelial cells, and a basal differentiation bias or failure of differentiation of cKit+ progenitors. High-risk luminal and myoepithelial cells are transcriptionally enriched for genes of the opposite lineage, inflammatory, and cancer-related pathways. Genetically high risk luminal epithelial cells also show evidence of accelerated age, by as much as four decades compared to their chronological age, using a breast specific biological clock comprised of measurements of methylation and expression of the luminal-specific ELF5 transcription factor. We have identified breast aging hallmarks that reflect a convergent biology of cancer susceptibility, regardless of the specific underlying genetic or age-dependent risk, or the associated breast cancer subtype. Citation Format: Masaru Miyano, Sundus Shalabi, Rosalyn W. Sayaman, Martha Stampfer, Victoria E. Seewaldt, Mark A. LaBarge. Accelerated biological age is a driver of cancer susceptibility in genetic high risk breast tissue [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 5682.

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8

Rodilla, Veronica, Alessandro Dasti, Mathilde Huyghe, Daniel Lafkas, Cécile Laurent, Fabien Reyal, and Silvia Fre. "Luminal Progenitors Restrict Their Lineage Potential during Mammary Gland Development." PLOS Biology 13, no. 2 (February 17, 2015): e1002069. http://dx.doi.org/10.1371/journal.pbio.1002069.

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9

Yamamoto, Shoji, Zhenhua Wu, Hege G. Russnes, Shinji Takagi, Guillermo Peluffo, Charles Vaske, Xi Zhao, et al. "JARID1B Is a Luminal Lineage-Driving Oncogene in Breast Cancer." Cancer Cell 25, no. 6 (June 2014): 762–77. http://dx.doi.org/10.1016/j.ccr.2014.04.024.

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10

Mohamed, Gadisti Aisha Nurulhijjah Binti, Nevena B. Ognjenovic, Sundis Mahmood, Sarah Min Kyung Lee, Brock C. Christensen, Kristen E. Muller, and Diwakar R. Pattabiraman. "Abstract 1602: Lineage plasticity enables low ER luminal tumors to evolve and gain basal-like traits." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1602. http://dx.doi.org/10.1158/1538-7445.am2022-1602.

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Abstract Stratifying breast cancer into specific molecular or histological subtypes aids in therapeutic decision-making and predicting outcomes, however, these subtypes may not be as distinct as previously thought. Patients with luminal-like, Estrogen Receptor (ER)-expressing tumors have better prognosis than patients with more aggressive, triple-negative or basal-like tumors. There is, however, a subset of luminal-like tumors that express lower levels of ER, which exhibit more basal-like features. Previous studies have suggested that triple negative, basal-like tumors may arise from a luminal cell-of-origin, but there are no definitive studies that identify the cell-of-origin of these low ER tumors. Analysis of 2208 invasive breast carcinomas from 2012-2020 revealed that 2% of tumors have low ER expression (less than 10% ER positive cells), which are mostly high-grade carcinomas and exhibit basal-like features. TCGA analysis revealed that tumors with lower ER expression (lowest quartile of ER expression) expressed higher basal signature genes as compared to tumors with higher levels of ER expression. This variation within the ER+ subtype and the emergence of basal-like characteristics within low ER tumors suggest that some luminal tumors may evolve into a more basal-like or triple-negative subtype. The luminal mouse mammary tumor, MMTV-PyMT, was used to model low ER human tumors and, similar to the patient tumor samples, basal-like tumor cells were also found within these tumors. Lineage tracing using tissue-specific and inducible Cre recombinase-based labelling was performed to elucidate the lineage-of-origin of these basal-like cells, revealing that these basal-like cells were derived from normal luminal epithelial cells, not basal cells. Our study uncovers the existence of luminal-basal plasticity within tumors of a low ER subtype that enables these cells to transition into a more basal-like state. Understanding the factors that enable this plasticity to occur may reveal opportunities to curb the evolution of more aggressive traits, potentially improving the way breast cancer is currently managed and treated. Citation Format: Gadisti Aisha Nurulhijjah Binti Mohamed, Nevena B. Ognjenovic, Sundis Mahmood, Sarah Min Kyung Lee, Brock C. Christensen, Kristen E. Muller, Diwakar R. Pattabiraman. Lineage plasticity enables low ER luminal tumors to evolve and gain basal-like traits [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 1602.

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11

Lafkas, Daniel, Veronica Rodilla, Mathilde Huyghe, Larissa Mourao, Hippokratis Kiaris, and Silvia Fre. "Notch3 marks clonogenic mammary luminal progenitor cells in vivo." Journal of Cell Biology 203, no. 1 (October 7, 2013): 47–56. http://dx.doi.org/10.1083/jcb.201307046.

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The identity of mammary stem and progenitor cells remains poorly understood, mainly as a result of the lack of robust markers. The Notch signaling pathway has been implicated in mammary gland development as well as in tumorigenesis in this tissue. Elevated expression of the Notch3 receptor has been correlated to the highly aggressive “triple negative” human breast cancer. However, the specific cells expressing this Notch paralogue in the mammary gland remain unknown. Using a conditionally inducible Notch3-CreERT2SAT transgenic mouse, we genetically marked Notch3-expressing cells throughout mammary gland development and followed their lineage in vivo. We demonstrate that Notch3 is expressed in a highly clonogenic and transiently quiescent luminal progenitor population that gives rise to a ductal lineage. These cells are capable of surviving multiple successive pregnancies, suggesting a capacity to self-renew. Our results also uncover a role for the Notch3 receptor in restricting the proliferation and consequent clonal expansion of these cells.

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12

Yamaguchi, Noritaka, Emi Ito, Sakura Azuma, Reiko Honma, Yuka Yanagisawa, Akira Nishikawa, Mika Kawamura, et al. "FoxA1 as a lineage-specific oncogene in luminal type breast cancer." Biochemical and Biophysical Research Communications 365, no. 4 (January 2008): 711–17. http://dx.doi.org/10.1016/j.bbrc.2007.11.064.

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13

Kim, Jiyoung, and René Villadsen. "Expression of Luminal Progenitor Marker CD117 in the Human Breast Gland." Journal of Histochemistry & Cytochemistry 66, no. 12 (July 13, 2018): 879–88. http://dx.doi.org/10.1369/0022155418788845.

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CD117 is a putative marker of luminal progenitor cells in the human breast. However, so far mapping the expression pattern of CD117 within the normal gland has not been reported. Here, we examined the anatomical distribution of CD117-expressing cells in lobular and ductal structures by immunohistochemistry. The presence of CD117-positive luminal cells could be divided into three distinct patterns: (1) contiguous, with coherent positive cells and rare negative cells interspaced; (2) patched, with a roughly equal frequency of positive and negative cells distributed focally; or (3) scattered, with few or no positive cells in the structure. Generally, a patched or scattered expression pattern was more frequent in lobules compared with ducts. Furthermore, an age-correlated increase in heterogeneity was observed. When comparing women below and above 21 years of age this heterogeneity was evident for both lobules and ducts. Although CD117-expression was generally segregated from luminal-lineage transcription factor GATA3-positive cells, some did co-express both markers. Finally, co-staining with Ki-67 revealed that a prominent part of cycling cells belonged to the CD117-positive population. Together these data demonstrate the presence of a CD117-expressing progenitor compartment with the capacity to replenish the luminal lineage of the breast gland.

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14

Liu, June, Laura E. Pascal, Sudhir Isharwal, Daniel Metzger, Raquel Ramos Garcia, Jan Pilch, Susan Kasper, et al. "Regenerated Luminal Epithelial Cells Are Derived from Preexisting Luminal Epithelial Cells in Adult Mouse Prostate." Molecular Endocrinology 25, no. 11 (November 1, 2011): 1849–57. http://dx.doi.org/10.1210/me.2011-1081.

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Abstract Determining the source of regenerated luminal epithelial cells in the adult prostate during androgen deprivation and replacement will provide insights into the origin of prostate cancer cells and their fate during androgen deprivation therapy. Prostate stem cells in the epithelial layer have been suggested to give rise to luminal epithelium. However, the extent of stem cell participation to prostate regrowth is not clear. In this report, using prostate-specific antigen-CreERT2-based genetic lineage marking/tracing in mice, preexisting luminal epithelial cells were shown to be a source of regenerated luminal epithelial cells in the adult prostate. Prostatic luminal epithelial cells could survive androgen deprivation and were capable of proliferating upon androgen replacement. Prostate cancer cells, typically exhibiting a luminal epithelial phenotype, may retain this intrinsic capability to survive and regenerate in response to changes in androgen signaling, providing part of the mechanism for the ultimate failure of androgen deprivation therapy in prostate cancer.

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15

Phoon, Yee Peng, Indira V. Chivukula, Yat Long Tsoi, Shigeaki Kanatani, Per Uhlén, Raoul Kuiper, and Urban Lendahl. "Notch activation in the mouse mammary luminal lineage leads to ductal hyperplasia and altered partitioning of luminal cell subtypes." Experimental Cell Research 395, no. 1 (October 2020): 112156. http://dx.doi.org/10.1016/j.yexcr.2020.112156.

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16

Seong, Jinwoo, Nam-Shik Kim, Jee-Ah Kim, Wonbin Lee, Ji-Yun Seo, Min Kyu Yum, Ji-Hoon Kim, et al. "Side branching and luminal lineage commitment by ID2 in developing mammary glands." Development 145, no. 14 (June 27, 2018): dev165258. http://dx.doi.org/10.1242/dev.165258.

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17

MacDougall, J. R., and L. M. Matrisian. "Targets of extinction: identification of genes whose expression is repressed as a consequence of somatic fusion between cells representing basal and luminal mammary epithelial phenotypes." Journal of Cell Science 113, no. 3 (February 1, 2000): 409–23. http://dx.doi.org/10.1242/jcs.113.3.409.

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The use of somatic cell hybrids has led to an increased understanding of the ‘negative’ regulation of cellular phenotype. Using somatic cell hybrids constructed between human breast cells that represent differing stages of malignancy but also display differing phenotypes from the same tissue, we present experimental results suggesting that luminal epithelial characteristics are controlled by repressive mechanisms. Fusion of HBL 100 cells, non-tumorigenic and characteristic of the basal cell lineage, with MCF-7 or MDA-MB-468 malignant breast cancer cells, characteristic of the luminal lineage, resulted in hybrid cells that displayed the phenotype of the HBL 100 cells. Using representational difference analysis, a panel of genes whose expression was repressed in the hybrid between HBL 100 and MDA-MB-468 was identified. This analysis revealed markers of luminal epithelial cells to be repressed, including Ep-CAM, cytokeratin 19 and E-cadherin. These markers were found to be coordinately re-expressed in variant hybrid cells indicating that the observed repression is reversible. Integrin (alpha)(v)(beta)(3) expression was found to be in mutual exclusivity to the luminal epithelial markers, thereby revealing a bidirectional ‘switch’ in the pattern of gene expression in this system. Finally, the expression of Ep-CAM was found to be lost in heterokaryons produced by fusion of HBL 100 and MCF-7 or MDA-MB-468 cells suggesting that the extinction of this gene in hybrid cells is the consequence of a trans-acting factor(s) synthesized by the HBL 100 cells. These data suggest that a number of markers of luminal cell differentiation in the mammary gland can be controlled through negative mechanisms and that such control of phenotype is highly coordinated.

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Jin, Shiying. "Bipotent stem cells support the cyclical regeneration of endometrial epithelium of the murine uterus." Proceedings of the National Academy of Sciences 116, no. 14 (March 14, 2019): 6848–57. http://dx.doi.org/10.1073/pnas.1814597116.

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The endometrial epithelium of the uterus regenerates periodically. The cellular source of newly regenerated endometrial epithelia during a mouse estrous cycle or a human menstrual cycle is presently unknown. Here, I have used single-cell lineage tracing in the whole mouse uterus to demonstrate that epithelial stem cells exist in the mouse uterus. These uterine epithelial stem cells provide a resident cellular supply that fuels endometrial epithelial regeneration. They are able to survive cyclical uterine tissue loss and persistently generate all endometrial epithelial lineages, including the functionally distinct luminal and glandular epithelia, to maintain uterine cycling. The uterine epithelial stem cell population also supports the regeneration of uterine endometrial epithelium post parturition. The 5-ethynyl-2′-deoxyuridine pulse-chase experiments further reveal that this stem cell population may reside in the intersection zone between luminal and glandular epithelial compartments. This tissue distribution allows these bipotent uterine epithelial stem cells to bidirectionally differentiate to maintain homeostasis and regeneration of mouse endometrial epithelium under physiological conditions. Thus, uterine function over the reproductive lifespan of a mouse relies on stem cell-maintained rhythmic endometrial regeneration.

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19

Sirka, Orit Katarina, Eliah R. Shamir, and Andrew J. Ewald. "Myoepithelial cells are a dynamic barrier to epithelial dissemination." Journal of Cell Biology 217, no. 10 (July 30, 2018): 3368–81. http://dx.doi.org/10.1083/jcb.201802144.

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The mammary epithelium is composed of an inner luminal and surrounding myoepithelial cell layer. The presence of cancer cells beyond the myoepithelium defines invasive breast cancer, yet the role of the myoepithelium during invasion remains unclear. We developed a 3D organotypic culture assay to model this process through lineage-specific expression of the prometastatic transcription factor Twist1. We sought to distinguish the functional role of the myoepithelium in regulating invasion and local dissemination. Myoepithelial-specific Twist1 expression induced cell-autonomous myoepithelial cell escape. Remarkably, luminal-specific Twist1 expression was rarely sufficient for escape. Time-lapse microscopy revealed that myoepithelial cells collectively restrain and reinternalize invading Twist1+ luminal cells. Barrier function correlated with myoepithelial abundance and required the expression of α-smooth muscle actin and P-cadherin. We next demonstrated that myoepithelial cells can restrain and recapture invasive cancer cells. Our data establish the concept of the myoepithelium as a dynamic barrier to luminal dissemination and implicate both smooth muscle contractility and intercellular adhesion in barrier function.

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Farabaugh, Susan M., Beate C. Litzenburger, Ashuvinee Elangovan, Geoffrey Pecar, Lauren Walheim, Jennifer M. Atkinson, and Adrian V. Lee. "IGF1R constitutive activation expands luminal progenitors and influences lineage differentiation during breast tumorigenesis." Developmental Biology 463, no. 1 (July 2020): 77–87. http://dx.doi.org/10.1016/j.ydbio.2020.04.007.

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21

Mu, Ping, Zeda Zhang, Matteo Benelli, Wouter R. Karthaus, Elizabeth Hoover, Chi-Chao Chen, John Wongvipat, et al. "SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer." Science 355, no. 6320 (January 5, 2017): 84–88. http://dx.doi.org/10.1126/science.aah4307.

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Some cancers evade targeted therapies through a mechanism known as lineage plasticity, whereby tumor cells acquire phenotypic characteristics of a cell lineage whose survival no longer depends on the drug target. We use in vitro and in vivo human prostate cancer models to show that these tumors can develop resistance to the antiandrogen drug enzalutamide by a phenotypic shift from androgen receptor (AR)–dependent luminal epithelial cells to AR-independent basal-like cells. This lineage plasticity is enabled by the loss of TP53 and RB1 function, is mediated by increased expression of the reprogramming transcription factor SOX2, and can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression. Thus, mutations in tumor suppressor genes can create a state of increased cellular plasticity that, when challenged with antiandrogen therapy, promotes resistance through lineage switching.

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Ryu, Won-Ji, Hyun-Yi Kim, Tae Yeong Kim, Yeona Choi, Hyun Ju Hahn, Seul-Gi Kim, Gun Min Kim, et al. "Abstract 6082: TP53-GATA3 mutation status predisposes luminal-to-basal subtype conversion in advanced breast cancer patients." Cancer Research 82, no. 12_Supplement (June 15, 2022): 6082. http://dx.doi.org/10.1158/1538-7445.am2022-6082.

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Abstract Background The molecular selective pressure on anti-tumor therapy drives lineage plasticity in several cancer types to develop drug resistance. The subtype conversion from luminal to triple-negative breast cancer (TNBC) subtype fuels endocrine resistance and disease aggressiveness. In this study, we analyzed mechanisms of luminal to basal subtype conversion by clinical sample sequencing and molecular study. Method We performed whole-exome sequencing (WES) of primary and metastatic tumor tissues from breast cancer patients with luminal to basal [from HR(+)/HER2(-) to TNBC] subtype conversion (experimental, n=14) and patients with subtype maintenance (luminal to luminal subtype, control, n= 36) after adjuvant endocrine therapy. For RNA-sequencing, the subset of patients (experimental, n=14; control n=7) was further analyzed. The differences in genetic alterations and gene expression were compared between two patient groups to identify genetic predictors of subtype conversion. We also manipulated genetic factors related to subtype conversion in MCF7 cells to identify molecular signaling to drive lineage change. Results In WES analysis, TP53 mutation was more frequently observed in luminal breast cancer patients with subtype conversion to TNBC [60% (12 out of 20 tissues in experimental group) versus 20% (8/40 tissues in control group)]. Whereas, GATA3 mutations were only observed in patients of subtype maintenance (0% versus 20%), and the mRNA level of GATA3 was downregulated after luminal-to-basal conversion. The TP53 and GATA3 mutations were both observed in the matched primary and metastatic tissues, suggesting that these mutations predisposed subtype conversion but were not acquired during the adjuvant endocrine therapy. In expression signature analysis, the patients with subtype conversion showed the upregulation of KRAS signaling and the suppression of GATA3 signature in metastatic TNBC tumors compared to primary luminal tumors. In primary tumors, RELA and MYC signatures were only upregulated in tumors that underwent subtype conversion later. We found ESR1 expression was decreased by knockdown of TP53 and GATA3 in MCF7 cells. The knockdown of TP53 and GATA3 also induced basal marker expressions, cytokeratin 5 and 14, in MCF7 cells. ESR1 expression and luminal markers were also decreased by GATA3 suppression in T47D harboring TP53 mutation. Conclusion In luminal-type breast cancer, the subtype conversion is the one of the major obstacles for their treatment and preventing recurrence. We found the genetic alterations of TP53 mutation was the key predisposing factor of luminal to basal subtype conversion, whereas GATA3 mutation is a protecting factor for subtype conversion in luminal breast cancers. Thus, targeting TP53-GATA3 axis would be a potential therapeutic strategy to overcome endocrine resistance and block the subtype conversion in luminal type breast cancer. Citation Format: Won-Ji Ryu, Hyun-Yi Kim, Tae Yeong Kim, Yeona Choi, Hyun Ju Hahn, Seul-Gi Kim, Gun Min Kim, Ja Seung Koo, Seung Il Kim, Joohyuk Sohn, Min Hwan Kim. TP53-GATA3 mutation status predisposes luminal-to-basal subtype conversion in advanced breast cancer patients [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 6082.

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Baker, Laura A., Holly Holliday, and Alexander Swarbrick. "ID4 controls luminal lineage commitment in normal mammary epithelium and inhibits BRCA1 function in basal-like breast cancer." Endocrine-Related Cancer 23, no. 9 (September 2016): R381—R392. http://dx.doi.org/10.1530/erc-16-0196.

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Inhibitor of differentiation (ID) proteins are key regulators of development and tumorigenesis. One member of this family, ID4, controls lineage commitment during mammary gland development by acting upstream of key developmental pathways. Recent evidence suggests an emerging role for ID4 as a lineage-dependent proto-oncogene that is overexpressed and amplified in a subset of basal-like breast cancers (BLBCs), conferring poor prognosis. Several lines of evidence suggest ID4 may suppress BRCA1 function in BLBC and in doing so, define a subset of BLBC patients who may respond to therapies traditionally used in BRCA1-mutant cancers. This review highlights recent advances in our understanding of the requirement for ID4 in mammary lineage commitment and the role for ID4 in BLBC. We address current shortfalls in this field and identify important areas of future research.

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24

Samocha, Alexandr, Hanna Doh, Kai Kessenbrock, and Jeroen P. Roose. "Unraveling Heterogeneity in Epithelial Cell Fates of the Mammary Gland and Breast Cancer." Cancers 11, no. 10 (September 24, 2019): 1423. http://dx.doi.org/10.3390/cancers11101423.

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Fluidity in cell fate or heterogeneity in cell identity is an interesting cell biological phenomenon, which at the same time poses a significant obstacle for cancer therapy. The mammary gland seems a relatively straightforward organ with stromal cells and basal- and luminal- epithelial cell types. In reality, the epithelial cell fates are much more complex and heterogeneous, which is the topic of this review. Part of the complexity comes from the dynamic nature of this organ: the primitive epithelial tree undergoes extensively remodeling and expansion during puberty, pregnancy, and lactation and, unlike most other organs, the bulk of mammary gland development occurs late, during puberty. An active cell biological debate has focused on lineage commitment to basal- and luminal- epithelial cell fates by epithelial progenitor and stem cells; processes that are also relevant to cancer biology. In this review, we discuss the current understanding of heterogeneity in mammary gland and recent insights obtained through lineage tracing, signaling assays, and organoid cultures. Lastly, we relate these insights to cancer and ongoing efforts to resolve heterogeneity in breast cancer with single-cell RNAseq approaches.

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Lee, Eunmi, Raziye Piranlioglu, Max S. Wicha, and Hasan Korkaya. "Plasticity and Potency of Mammary Stem Cell Subsets During Mammary Gland Development." International Journal of Molecular Sciences 20, no. 9 (May 13, 2019): 2357. http://dx.doi.org/10.3390/ijms20092357.

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It is now widely believed that mammary epithelial cell plasticity, an important physiological process during the stages of mammary gland development, is exploited by the malignant cells for their successful disease progression. Normal mammary epithelial cells are heterogeneous and organized in hierarchical fashion, in which the mammary stem cells (MaSC) lie at the apex with regenerative capacity as well as plasticity. Despite the fact that the majority of studies supported the existence of multipotent MaSCs giving rise to both basal and luminal lineages, others proposed lineage restricted unipotent MaSCs. Consistent with the notion, the latest research has suggested that although normal MaSC subsets mainly stay in a quiescent state, they differ in their reconstituting ability, spatial localization, and molecular and epigenetic signatures in response to physiological stimuli within the respective microenvironment during the stages of mammary gland development. In this review, we will focus on current research on the biology of normal mammary stem cells with an emphasis on properties of cellular plasticity, self-renewal and quiescence, as well as the role of the microenvironment in regulating these processes. This will include a discussion of normal breast stem cell heterogeneity, stem cell markers, and lineage tracing studies.

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Beltran, Himisha, and Francesca Demichelis. "Therapy considerations in neuroendocrine prostate cancer: what next?" Endocrine-Related Cancer 28, no. 8 (August 1, 2021): T67—T78. http://dx.doi.org/10.1530/erc-21-0140.

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Lineage plasticity and histologic transformation to small cell neuroendocrine prostate cancer (NEPC) is an increasingly recognized mechanism of treatment resistance in advanced prostate cancer. This is associated with aggressive clinical features and poor prognosis. Recent work has identified genomic, epigenomic, and transcriptome changes that distinguish NEPC from prostate adenocarcinoma, pointing to new mechanisms and therapeutic targets. Treatment-related NEPC arises clonally from prostate adenocarcinoma during the course of disease progression, retaining early genomic events and acquiring new molecular features that lead to tumor proliferation independent of androgen receptor activity, and ultimately demonstrating a lineage switch from a luminal prostate cancer phenotype to a small cell neuroendocrine carcinoma. Identifying the subset of prostate tumors most vulnerable to lineage plasticity and developing strategies for earlier detection and intervention for patients with NEPC may ultimately improve prognosis. Clinical trials focused on drug targeting of the lineage plasticity process and/or NEPC will require careful patient selection. Here, we review emerging targets and discuss biomarker considerations that may be informative for the design of future clinical studies.

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Chiang, Huai-Chin, Richard Elledge, Paula Larson, Ismail Jatoi, Rong Li, and Yanfen Hu. "Effects of Radiation Therapy on Breast Epithelial Cells in BRCA1/2 Mutation Carriers." Breast Cancer: Basic and Clinical Research 9 (January 2015): BCBCR.S26774. http://dx.doi.org/10.4137/bcbcr.s26774.

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Women carrying BRCA1 and BRCA2 mutations have significantly elevated risk of developing breast and ovarian cancers. BRCA1-associated breast cancer likely originates from progenitors of the luminal epithelial lineage. Recent studies indicate that radiation therapy (RT) for BRCA1 cancer patients is associated with lower incidence of developing subsequent ipsilateral breast cancer. In the current study, we analyzed tumor-free breast tissue procured via prophylactic bilateral mastectomy from three BRCA1 and one BRCA2 mutation carriers, who had been previously treated with RT for unilateral breast cancers. Freshly isolated breast cells from the irradiated and nonirradiated breast tissue of the same individuals were subjected to flow cytometry, using established cell-surface markers. Two out of the three BRCA1 carriers and one BRCA2 carrier exhibited significantly diminished luminal cell population in the irradiated breast versus the nonirradiated side. There was also RT-associated reduction in the colony-forming ability of the breast epithelial cells. Our finding suggests that prior RT could result in the depletion of the luminal epithelial compartment and thus reduced incidence of BRCA1/2-associated breast cancer.

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Taylor-Papadimitriou, J., M. Stampfer, J. Bartek, A. Lewis, M. Boshell, E. B. Lane, and I. M. Leigh. "Keratin expression in human mammary epithelial cells cultured from normal and malignant tissue: relation to in vivo phenotypes and influence of medium." Journal of Cell Science 94, no. 3 (November 1, 1989): 403–13. http://dx.doi.org/10.1242/jcs.94.3.403.

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The luminal and basal epithelial cells in the human mammary gland can be distinguished in tissue sections on the basis of the pattern of keratins they express. Moreover, the invasive cells in primary carcinomas show a keratin profile that corresponds to that of the dominant luminal cell (7, 8, 18, 19). When homogeneous populations of luminal epithelial cells from milk or from breast cancer metastases are cultured the profile of keratin expression seen in vivo is maintained. We have therefore used monospecific antibodies reactive with individual keratins to examine the phenotype of cells cultured in three different media from reduction mammoplasty tissue that contains both luminal and basal cells. The phenotype of cells cultured from primary breast cancers in one of these media (MCDB170) has also been examined. In characterizing cell phenotypes, antibodies to a polymorphic epithelial mucin (PEM) expressed in vivo by luminal cells, and to smooth muscle (a) actin, expressed in vivo by basal cells, have also been used. Our results show that proliferation of different cell phenotypes is selected for in different media. In milk mix (MX) developed for growth of luminal cells from milk, only the luminal cell phenotype proliferates (for only 1 or 2 passages). In medium MCDB 170, which was developed for long-term growth of human mammary epithelial cells from reduction mammoplasty organoids, cells from the basal layer proliferate, while in MM medium the basal phenotype dominates, but a few cells with the luminal phenotype are found. Around passage 3, in medium MCDB 170, most cells senesce and a subpopulation of cells proliferates on further passage. These cells retain expression of the basal epithelial keratins but also express some features characteristic of luminal epithelial cells, suggesting that the basal layer may contain a stem cell that can develop along the luminal lineage. In culture, however, they do not express keratin 19, which in vivo is a feature of the fully differentiated luminal cell. The cells cultured from primary breast cancer in medium MCDB 170 have a similar keratin profile to that of the normal cells cultured in this medium. They do not express keratin 19, even though the invasive cells in primary cancers homogeneously express this keratin in vivo. The invasive phenotype, which in its keratin profile corresponds to the differentiated luminal cell and that of the metastatic cancer lines, cannot be cultured from primary breast cancers using MX, which supports proliferation of the corresponding normal cell.

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Rusidzé, Mariam, Marine Adlanmérini, Elodie Chantalat, I. Raymond-Letron, Surya Cayre, Jean-François Arnal, Marie-Ange Deugnier та Françoise Lenfant. "Estrogen receptor-α signaling in post-natal mammary development and breast cancers". Cellular and Molecular Life Sciences 78, № 15 (22 червня 2021): 5681–705. http://dx.doi.org/10.1007/s00018-021-03860-4.

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Abstract17β-estradiol controls post-natal mammary gland development and exerts its effects through Estrogen Receptor ERα, a member of the nuclear receptor family. ERα is also critical for breast cancer progression and remains a central therapeutic target for hormone-dependent breast cancers. In this review, we summarize the current understanding of the complex ERα signaling pathways that involve either classical nuclear “genomic” or membrane “non-genomic” actions and regulate in concert with other hormones the different stages of mammary development. We describe the cellular and molecular features of the luminal cell lineage expressing ERα and provide an overview of the transgenic mouse models impacting ERα signaling, highlighting the pivotal role of ERα in mammary gland morphogenesis and function and its implication in the tumorigenic processes. Finally, we describe the main features of the ERα-positive luminal breast cancers and their modeling in mice.

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30

Zhou, Jianjun, Lionel Feigenbaum, Carole Yee, Hongbin Song, and Clayton Yates. "Mouse Prostate Epithelial Luminal Cells Lineage Originate in the Basal Layer Where the Primitive Stem/Early Progenitor Cells Reside: Implications for Identifying Prostate Cancer Stem Cells." BioMed Research International 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/913179.

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Prostate stem cells are thought to be responsible for generation of all prostate epithelial cells and for tissue maintenance. The lineage relationship between basal and luminal cells in the prostate is not well clarified. We developed a mouse model to trace cell fate and a mouse model with a slowly cycling cell label to provide insight into this question. The results obtained indicate that putative mouse prostate stem cells are likely to reside in the basal layer.

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31

Falk, P., K. A. Roth, and J. I. Gordon. "Lectins are sensitive tools for defining the differentiation programs of mouse gut epithelial cell lineages." American Journal of Physiology-Gastrointestinal and Liver Physiology 266, no. 6 (June 1, 1994): G987—G1003. http://dx.doi.org/10.1152/ajpgi.1994.266.6.g987.

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We have used histochemical methods to survey the cellular patterns of binding of a panel of 45 lectins with well-defined carbohydrate specificities to sections prepared from various regions of the gastric-to-colonic axis of fetal, neonatal, and adult FVB/N mouse gut. The results suggest that lectins can be used as remarkably sensitive tools to describe the differentiation programs of gastric and intestinal epithelial cell lineages as a function of their position along the cephalocaudal axis of the gut and as a function of developmental stage. Studies of intestinal isografts and transgenic mice that express Simian virus-40 T antigen in enterocytes suggest that many of these cell lineage-specific and spatial patterns of glycoconjugate production can be established and maintained in the absence of exposure to luminal contents and in the presence of specific proliferative abnormalities. This lectin panel should be useful for operationally defining subpopulations of the principal gut epithelial cell lineages in normal strains of mice, for describing variations in gut epithelial cell differentiation programs in mutant and transgenic mice, and for recovering specific epithelial cell lineages or subpopulations.

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32

Rybtsov, Stanislav, Malgorzata Sobiesiak, Samir Taoudi, Céline Souilhol, Jordi Senserrich, Anna Liakhovitskaia, Andrejs Ivanovs, Jon Frampton, Suling Zhao, and Alexander Medvinsky. "Hierarchical organization and early hematopoietic specification of the developing HSC lineage in the AGM region." Journal of Experimental Medicine 208, no. 6 (May 30, 2011): 1305–15. http://dx.doi.org/10.1084/jem.20102419.

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The aorta-gonad-mesonephros region plays an important role in hematopoietic stem cell (HSC) development during mouse embryogenesis. The vascular endothelial cadherin+ CD45+ (VE-cad+CD45+) population contains the major type of immature pre-HSCs capable of developing into long-term repopulating definitive HSCs. In this study, we developed a new coaggregation culture system, which supports maturation of a novel population of CD45-negative (VE-cad+CD45−CD41+) pre-HSCs into definitive HSCs. The appearance of these pre-HSCs precedes development of the VE-cad+CD45+ pre-HSCs (termed here type I and type II pre-HSCs, respectively), thus establishing a hierarchical directionality in the developing HSC lineage. By labeling the luminal surface of the dorsal aorta, we show that both type I and type II pre-HSCs are distributed broadly within the endothelial and subendothelial aortic layers, in contrast to mature definitive HSCs which localize to the aortic endothelial layer. In agreement with expression of CD41 in pre-HSCs, in vivo CD41-Cre–mediated genetic tagging occurs in embryonic pre-HSCs and persists in all lymphomyeloid lineages of the adult animal.

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33

Blee, Alexandra M., Yundong He, Yinhui Yang, Zhenqing Ye, Yuqian Yan, Yunqian Pan, Tao Ma, et al. "TMPRSS2-ERG Controls Luminal Epithelial Lineage and Antiandrogen Sensitivity in PTEN and TP53-Mutated Prostate Cancer." Clinical Cancer Research 24, no. 18 (May 29, 2018): 4551–65. http://dx.doi.org/10.1158/1078-0432.ccr-18-0653.

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34

Deugnier, Marie-Ange, Marisa M. Faraldo, Bassam Janji, Patricia Rousselle, Jean Paul Thiery, and Marina A. Glukhova. "EGF controls the in vivo developmental potential of a mammary epithelial cell line possessing progenitor properties." Journal of Cell Biology 159, no. 3 (November 11, 2002): 453–63. http://dx.doi.org/10.1083/jcb.200207138.

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The bilayered mammary epithelium comprises a luminal layer of secretory cells and a basal layer of myoepithelial cells. Numerous data suggest the existence of self-renewing, pluripotent mammary stem cells; however, their molecular characteristics and differentiation pathways are largely unknown. BC44 mammary epithelial cells in culture, display phenotypic characteristics of basal epithelium, i.e., express basal cytokeratins 5 and 14 and P-cadherin, but no smooth muscle markers. In vivo, after injection into the cleared mammary fat pad, these cells gave rise to bilayered, hollow, alveolus-like structures comprising basal cells expressing cytokeratin 5 and luminal cells positive for cytokeratin 8 and secreting β-casein in a polarized manner into the lumen. The persistent stimulation of EGF receptor signaling pathway in BC44 cells in culture resulted in the loss of the in vivo morphogenetic potential and led to the induction of active MMP2, thereby triggering cell scattering and motility on laminin 5. These data (a) suggest that BC44 cells are capable of asymmetric division for self-renewal and the generation of a differentiated progeny restricted to the luminal lineage; (b) clarify the function of EGF in the control of the BC44 cell phenotypic plasticity; and (c) suggest a role for this phenomenon in the mammary gland development.

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Dong, Jian-De, Jin-Hong Huang, Feng Gao, Zhao-Hui Zhu, and Jian Zhang. "Mesenchymal stem cell-based tissue engineering of small-diameter blood vessels." Vascular 19, no. 4 (July 22, 2011): 206–13. http://dx.doi.org/10.1258/vasc.2011.oa0283.

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The aim of the study was to construct small-diameter vascular grafts using canine mesenchymal stem cells (cMSCs) and a pulsatile flow bioreactor. cMSCs were isolated from canine bone marrow and expanded ex vivo. cMSCs were then seeded onto the luminal surface of decellularized arterial matrices, which were further cultured in a pulsatile flow bioreactor for four days. Immunohistochemical staining and scanning electron microscopy was performed to characterize the tissue-engineered blood vessels. cMSCs were successfully seeded onto the luminal surface of porcine decellularized matrices. After four-day culture in the pulsatile flow bioreactor, the cells were highly elongated and oriented to the flow direction. Immunohistochemistry demonstrated that the cells cultured under pulsatile flow expressed Von Willebrand factor, an endothelial cell marker. In conclusion, cMSCs seeded onto decellularized arterial matrices could differentiate into endothelial lineage after culturing in a pulsatile flow bioreactor, which provides a novel approach for tissue engineering of small-diameter blood vessels.

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36

Li, Yanjing, Yiping He, William Butler, Lingfan Xu, Yan Chang, Kefeng Lei, Hong Zhang, et al. "Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer." Science Translational Medicine 11, no. 521 (December 4, 2019): eaax0428. http://dx.doi.org/10.1126/scitranslmed.aax0428.

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Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR+ luminal tumor cells and AR− neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR+ luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity.

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Middelhoff, Moritz, C. Benedikt Westphalen, Yoku Hayakawa, Kelley S. Yan, Michael D. Gershon, Timothy C. Wang, and Michael Quante. "Dclk1-expressing tuft cells: critical modulators of the intestinal niche?" American Journal of Physiology-Gastrointestinal and Liver Physiology 313, no. 4 (October 1, 2017): G285—G299. http://dx.doi.org/10.1152/ajpgi.00073.2017.

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Dclk1-expressing tuft cells constitute a unique intestinal epithelial lineage that is distinct from enterocytes, Paneth cells, goblet cells, and enteroendocrine cells. Tuft cells express taste-related receptors and distinct transcription factors and interact closely with the enteric nervous system, suggesting a chemosensory cell lineage. In addition, recent work has shown that tuft cells interact closely with cells of the immune system, with a critical role in the cellular regulatory network governing responses to luminal parasites. Importantly, ablation of tuft cells severely impairs epithelial proliferation and tissue regeneration after injury, implicating tuft cells in the modulation of epithelial stem/progenitor function. Finally, tuft cells expand during chronic inflammation and in preneoplastic tissues, suggesting a possible early role in inflammation-associated tumorigenesis. Hence, we outline and discuss emerging evidence that strongly supports tuft cells as key regulatory cells in the complex network of the intestinal microenvironment.

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Hoffmann, Christian, David A. Hill, Nana Minkah, Thomas Kirn, Amy Troy, David Artis, and Frederic Bushman. "Community-Wide Response of the Gut Microbiota to Enteropathogenic Citrobacter rodentium Infection Revealed by Deep Sequencing." Infection and Immunity 77, no. 10 (July 27, 2009): 4668–78. http://dx.doi.org/10.1128/iai.00493-09.

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ABSTRACT We investigated the spatial and temporal response of the murine gut microbiome to infection with Citrobacter rodentium, an attaching-and-effacing bacterium that provokes innate and adaptive immune responses, resulting in transient bacterial colitis. Previous studies have suggested that C. rodentium-induced inflammation is associated with an increased abundance of Enterobacteriaceae. We report here a deeper analysis of this model using DNA bar coding and 454 pyrosequencing to characterize 101,894 partial 16S rRNA gene sequences from 85 microbial samples from tissue-adhered and luminal bacteria of the cecum, proximal colon, and distal colon, which allowed us to identify previously unappreciated spatial and kinetic changes in multiple bacterial lineages. The deep sequencing data revealed that C. rodentium was most abundantly associated with the cecal mucosa at day 9 postinfection and then diminished in abundance, providing the first reported use of deep sequencing to track a pathogen in vivo through the course of infection. Notable changes were associated with both the mucosally adhered and luminal microbiota at both day 9 and day 14 postinfection. Alterations in abundance were seen for Proteobacteria, Deferribacteres, Clostridia, and others; however, changes in Enterobacteriaceae could be accounted for by the presence of C. rodentium itself, which is a member of this family. The Lactobacillus group decreased in abundance during infection, which may be important for pathogenesis because members of this lineage modulate the composition of the gut microbiota and are used as probiotics. Thus, deep sequencing provides previously inaccessible information on how Citrobacter infection and clearance reshapes the gut microbial community in space and time.

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Chan, Joseph M., Wouter R. Karthaus, Manu Setty, Jillian R. Love, Samir Zaidi, Jimmy Zhao, Zi-ning Choo, et al. "Abstract 1594: Reversal of lineage plasticity in RB1/TP53-deleted prostate cancer through FGFR and Janus kinase inhibition." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1594. http://dx.doi.org/10.1158/1538-7445.am2022-1594.

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Abstract The inherent plasticity of tumor cells provides a mechanism of resistance to many molecularly targeted therapies, exemplified by adeno-to-neuroendocrine lineage transitions seen in prostate and lung cancer. Here we investigate the root cause of this lineage plasticity in a primary murine prostate organoid model that mirrors the lineage transition seen in patients. These cells lose luminal identity within weeks following deletion of Trp53 and Rb1, ultimately acquiring an Ar-negative, Syp+ phenotype after orthotopic in vivo transplantation. We performed single-cell transcriptomic analysis of a time-course experiment on the prostate organoid following Trp53 and Rb1 deletion. Critical to this study, we developed SEACells, a method that enumerates distinct, highly granular cell states, allowing for robust transcriptomic quantification. Leveraging the SEACell platform, we developed several graph-based computational approaches based on Markov absorption, diffusion maps, and attributed stochastic block models to quantify dynamic changes in plasticity. These quantitative models independently confirmed rapid collapse of cell-type fidelity in the form of a mixed luminal-basal phenotype following tumor suppressor gene deletion. These methods compute metrics for plasticity that we correlated to candidate driver gene programs. Among the strongest plasticity correlates, Jak-Stat and Fgfr signaling stood out as gene programs activated early in the time-course prior to any corresponding morphological changes. We further developed a regression-based approach to nominate ligand-receptor interactions that activate downstream Jak-Stat signaling, which identified Fgf-Fgfr interactions that were functionally validated with growth factor addition and pharmacological inhibition. Most strikingly, genetic or pharmacologic inhibition of Jak1/2 in combination with Fgfr blockade not only reversed the plastic state and restored organoids to their wild-type morphology, but also re-sensitized drug-resistant cells to antiandrogen therapy in models with residual AR expression. We additionally confirm early activation of Jak/Stat transcriptional programs in an Rb1/Trp53/Pten-deleted genetically engineered mouse model undergoing substantial cell-type diversification under plasticity in the context of the tumor microenvironment. Collectively, we show that lineage plasticity initiates quickly as a largely cell-autonomous process that is further increased in the in vivo setting, and through newly developed computational approaches, we identify a pharmacological strategy that restores lineage identity using clinical grade inhibitors. Citation Format: Joseph M. Chan, Wouter R. Karthaus, Manu Setty, Jillian R. Love, Samir Zaidi, Jimmy Zhao, Zi-ning Choo, Sitara Persad, Justin LaClair, Kayla E. Lawrence, Ojasvi Chaudhary, Ignas Masilionis, Linas Mazutis, Ronan Chaligne, Dana Pe'er, Charles Sawyers. Reversal of lineage plasticity in RB1/TP53-deleted prostate cancer through FGFR and Janus kinase inhibition [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 1594.

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Kwon, Oh-Joon, Li Zhang, and Li Xin. "Stem Cell Antigen-1 Identifies a Distinct Androgen-Independent Murine Prostatic Luminal Cell Lineage with Bipotent Potential." STEM CELLS 34, no. 1 (October 27, 2015): 191–202. http://dx.doi.org/10.1002/stem.2217.

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Aikawa, Shizu, Jia Yuan, Amanda Dewar, Xiaofei Sun, and Sudhansu K. Dey. "Scribble promotes alveologenesis in the pregnant mammary gland for milk production." Reproduction 159, no. 6 (May 2020): 719–31. http://dx.doi.org/10.1530/rep-20-0108.

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Mammary glands are comprised of ducts and terminal lobules that form tree-like structures. Luminal epithelial cells in these lobules undergo differentiation into alveolar cells in pregnancy to support milk production. This study reveals that Scribble (SCRIB), a scaffold protein expressed in progesterone receptor (PGR)-positive cells, plays a critical role in mammary gland alveologenesis in mice. We conditionally deleted Scrib using a Pgr-Cre driver. PGR is heterogeneously expressed throughout the luminal epithelium. Scrib loss in mammary glands by Pgr-Cre (Scribf/fPgrCre/+) shows inefficient alveologenesis and terminal end bud (TEB)-like morphology during pregnancy, resulting in poor milk production and subsequent death of pups after delivery. The differentiation of PGR-positive epithelial cells into Elf5-expressing alveolar cells is defective in Scribf/fPgrCre/+ mice. These changes are reflected in reduced activation of JAK2 and PAK1, resulting in downregulation of pSTAT5, a critical transcriptional factor for alveologenesis. These results provide evidence that SCRIB impacts PGR-positive cell lineage during alveologenesis, which impacts milk production and the health of offspring.

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Reisz, Peter, Andrew Tracey, Fengshen Kuo, Jasmine Thomas, Timothy Nguyen Clinton, Andrew Thomas Lenis, Hong Truong, et al. "Single cell RNA sequencing of upper tract urothelial carcinoma to reveal significant heterogeneity of the tumor and immune microenvironment." Journal of Clinical Oncology 39, no. 6_suppl (February 20, 2021): 484. http://dx.doi.org/10.1200/jco.2021.39.6_suppl.484.

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484 Background: Upper tract urothelial carcinoma (UTUC) comprises 5-10% of urothelial malignancies but demonstrates unique clinical and molecular characteristics compared to urothelial carcinoma of the bladder. Prior investigations have used bulk profiling of tumor tissue to identify molecular subtypes, classifying the majority of UTUC as luminal and T-cell depleted. However, bulk sequencing does not allow for analysis of the significant heterogeneity known to be present in urothelial tumors. Single-cell RNA sequencing (scRNA-seq) allows examination of intra-tumoral heterogeneity, clonality, and the complex interactions of the immune tumor microenvironment (TME). We sought to apply this technology to better characterize UTUC and the TME. Methods: Single cell RNA sequencing (scRNA-seq) was performed on nine UTUC tissue specimens from six different patients collected fresh via ureteroscopic biopsy using an established institutional process and the 10X Genomics platform. Sequencing reads were normalized and analyzed using R/Seurat package. We assessed the composition of each tumor specimen with known marker genes for molecular subtypes (luminal, basal, squamous, EMT, and claudin-low). We then assessed the composition of immune cells in each specimen using known marker genes. We compared high- and low-grade specimens by subtype composition and immune cell infiltrates. Results: Lineage density analyses demonstrate the intra- and inter-tumoral heterogeneity of the nine endoscopic samples analyzed by molecular subtype composition. There is higher expression of luminal and claudin-low subtypes across all samples. The high-grade samples have higher expression of squamous markers. There is significant heterogeneity of immune cell infiltrates in seven specimens (two specimens were excluded due to low CD45+ cell counts). There is higher macrophage infiltration in high-grade samples, which was the only significant difference (Wilcoxon two-sided p-value = 0.05). Conclusions: This is the first known study using scRNA-seq expression analysis to characterize the notable heterogeneity of high and low-grade UTUC and the associated TME. Lineage density analysis demonstrates high luminal gene expression across samples, which has been demonstrated on prior bulk sequencing studies. The immune TME is also heterogeneous, with notable increased infiltration of macrophages in high-grade disease. There are unique limitations to performing and analyzing scRNA-seq of fresh UTUC tissue specimens, thus data should be interpreted cautiously. However, this study demonstrates the marked heterogeneity of UTUC tumors and frames our current approaches to bulk molecular subtyping of urothelial cancers and immune deconvolution. Further high-resolution studies are needed to characterize UTUC and inform bulk-sequencing efforts.

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Choi, Bo-Hyun, Vipin Rawat, Jenny Högström, Philippa A. Burns, Kelly O. Conger, Mete Emir Ozgurses, Jaymin M. Patel, et al. "Lineage-specific silencing of PSAT1 induces serine auxotrophy and sensitivity to dietary serine starvation in luminal breast tumors." Cell Reports 38, no. 3 (January 2022): 110278. http://dx.doi.org/10.1016/j.celrep.2021.110278.

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44

Kwon, Oh-Joon, Li Zhang, Deyong Jia, Zhicheng Zhou, Zhouyihan Li, Michael Haffner, John K. Lee, Lawrence True, Colm Morrissey, and Li Xin. "De novo induction of lineage plasticity from human prostate luminal epithelial cells by activated AKT1 and c-Myc." Oncogene 39, no. 48 (October 2, 2020): 7142–51. http://dx.doi.org/10.1038/s41388-020-01487-6.

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45

Zhou, Jiaojiao, Qishan Chen, Yiheng Zou, Shu Zheng, and Yiding Chen. "Stem Cells and Cellular Origins of Mammary Gland: Updates in Rationale, Controversies, and Cancer Relevance." Stem Cells International 2019 (January 8, 2019): 1–12. http://dx.doi.org/10.1155/2019/4247168.

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Evidences have supported the pivotal roles of stem cells in mammary gland development. Many molecular markers have been identified to characterize mammary stem cells. Cellular fate mapping of mammary stem cells by lineage tracing has put unprecedented insights into the mammary stem cell biology, which identified two subtypes of mammary stem cells, including unipotent and multipotent, which specifically differentiate to luminal or basal cells. The emerging single-cell sequencing profiles have given a more comprehensive understanding on the cellular hierarchy and lineage signatures of mammary epithelium. Besides, the stem cell niche worked as an essential regulator in sustaining the functions of mammary stem cells. In this review, we provide an overview of the characteristics of mammary stem cells. The cellular origins of mammary gland are discussed to understand the stem cell heterogeneity and their diverse differentiations. Importantly, current studies suggested that the breast cancer stem cells may originate from the mammary stem cells after specific mutations, indicating their close relationships. Here, we also outline the recent advances and controversies in the cancer relevance of mammary stem cells.

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46

Cottone, Gannon, Mariana Bustamante Eduardo, Shivangi Yadav, Seema Khan, and Susan Clare. "Abstract P6-11-08: Non-transformed breast epithelial cells show neural-like gene signature after lipid exposure." Cancer Research 83, no. 5_Supplement (March 1, 2023): P6–11–08—P6–11–08. http://dx.doi.org/10.1158/1538-7445.sabcs22-p6-11-08.

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Abstract Introduction: The identification of women specifically at risk for estrogen receptor negative breast cancer (ER-BC) and the targeted treatment of this disease are significantly unmet clinical needs. To that end, we analyzed the gene expression profiles of epithelial cells from the contralateral unaffected breasts (CUBs) of BC patients and identified a lipid metabolism gene signature, which was enriched in the CUBs of women with ER-negative BC (PMID: 28263391). Subsequent experiment revealed that exposure of non-transformed breast epithelial cells to lipid results in significant changes gene expression, chromatin accessibility and histone posttranslational modifications (PMID: 35508495). Several of the upregulated genes are hallmarks of the various fates of vagal neural crest: Neural, neurogenic and mesenchymal lineages. We hypothesize that lipid exposure imparts a survival advantage of stem-like cells, that lipid-induced epigenetic changes lead to a neural crest-like transcription signature and that these genes are not expressed normally in the breast. Methods: MCF10A cells were exposed to vehicle or octanoic acid (OA) for 24 hours. Gene expression was assayed by RNA-seq and OA responsive genes were identified (PMID: 35508495). Single-cell RNA sequencing (scRNA-seq) data from 14 human reduction mammoplasties (RM) was obtained from a publicly accessible data set (PMID: 34031589). The scRNA data was clustered and identified by unsupervised clustering (Seurat, v3.4.1) using cell-type markers curated using Supplementary table 2 from (PMID: 34031589). The bulk RNA-seq data from the OA treated cells was deconvoluted to cell-lineages using Bisque. The most significant upregulated VNC neural/neuronal/mesenchymal genes from the gene expression analysis were then plotted on the lineage clusters using FeaturePlot to determine if these markers are found in the normal breast epithelium, or other cell lineages. The plots were then filtered and re-clustered to look at basal-luminal cell types only. We utilized a second resource, a web-application for snATAC-seq data from various stages of mouse mammary development developed by the Wahl lab (https://wahl-lab-salk.shinyapps.io/Mammary_snATAC/), to query these same genes. Results: Deconvolution of the bulk RNA-sequencing data revealed a transition to a pericyte transcription program following exposure to OA. Nerve growth factor (NGF) was found to be expressed in pericytes while nerve growth factor receptor (NGFR) was found within the basal epithelial cell lineage. Genes overexpressed in the VNC neural cluster and overexpressed in the OA-exposed MCF10 cells, PPP1R1C (2.39x, adj p=1.6E-5), FOXD3 (6.7x, adj p=6.7E-10), DIO3 (5.9x, adj p=3.9E-6) and MOXD3 (4.2x, adj p=1.5E-23) all evidence little to no expression in the normal breast but are observed in murine fetal mammary stem cells. Schwann cell precursor (SCP) markers, CDH19 and ROPN1, significantly upregulated in OA treated cells: 5.4x and 1.6x, respectively, exhibited low expression in luminal progenitors but in the mouse were observed in the mammary stroma. CDH19, a gene exclusive to SCPs, is expressed in stroma following murine birth. PRRX1, a key regulator of the VNC mesenchymal cell fate cluster, is 9.3-fold (p adj=4.9E-49) overexpressed in the OA treated cells, expressed strongly in pericytes and stroma and to a lesser extent in basal epithelial cells of the normal human breast and stroma of the murine mammary gland. Conclusions: Treatment of non-transformed mammary epithelial cells with lipid, specifically OA, shows significant upregulation of multiple VNC genes associated with both neural and mesenchymal fate. scRNA-seq from RM patients reveals that many of these same markers are either found in non-epithelial cell clusters or are found with low expression in luminal mammary lineages (both progenitors and mature). Citation Format: Gannon Cottone, Mariana Bustamante Eduardo, Shivangi Yadav, Seema Khan, Susan Clare. Non-transformed breast epithelial cells show neural-like gene signature after lipid exposure [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-11-08.

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Evers, B. M., J. A. Ehrenfried, X. Wang, C. M. Townsend, and J. C. Thompson. "Temporal-specific and spatial-specific patterns of neurotensin gene expression in the small bowel." American Journal of Physiology-Gastrointestinal and Liver Physiology 267, no. 5 (November 1, 1994): G875—G882. http://dx.doi.org/10.1152/ajpgi.1994.267.5.g875.

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Expression of the neurotensin/neuromedin N (NT/N) gene is developmentally regulated in a temporal- and spatial-specific pattern in the small bowel. The purpose of our study was to determine 1) whether the temporal expression of NT/N could be altered by ectopic placement of small bowel and 2) whether the spatial-specific expression of NT/N could be altered by different diets. We found that the relative temporal pattern of NT/N expression was unchanged in rat jejunal and ileal xenografts implanted into the flanks of athymic nude mice. To determine whether the spatial-specific pattern of NT/N expression could be altered by different luminal nutrients, 28-day-old rats were randomized to receive chow or chemically defined liquid diets for 60 days at which time the jejunoileum was divided into eight equal segments, and NT/N expression was analyzed. The normal pattern of increasing levels of NT/N mRNA along the jejunum-to-ileum axis was not altered by any of the liquid diets. In contrast to NT/N, we found that expression of sucrase-isomaltase varied greatly depending on both location and type of luminal nutrients. We conclude that the strict temporal- and spatial-specific pattern of NT/N expression is not affected by either location or luminal contents, thus suggesting an intrinsic program of NT/N gene expression. Furthermore, we speculate that the NT/N gene may provide a useful endocrine paradigm to investigate the factors regulating the establishment and maintenance of certain cell lineage-specific patterns along the cephalocaudal axis of the gut.

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Pénzes, Judit J., William Marciel de Souza, Mavis Agbandje-McKenna, and Robert J. Gifford. "An Ancient Lineage of Highly Divergent Parvoviruses Infects both Vertebrate and Invertebrate Hosts." Viruses 11, no. 6 (June 6, 2019): 525. http://dx.doi.org/10.3390/v11060525.

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Chapparvoviruses (ChPVs) comprise a divergent, recently identified group of parvoviruses (family Parvoviridae), associated with nephropathy in immunocompromised laboratory mice and with prevalence in deep sequencing results of livestock showing diarrhea. Here, we investigate the biological and evolutionary characteristics of ChPVs via comparative in silico analyses, incorporating sequences derived from endogenous parvoviral elements (EPVs) as well as exogenous parvoviruses. We show that ChPVs are an ancient lineage within the Parvoviridae, clustering separately from members of both currently established subfamilies. Consistent with this, they exhibit a number of characteristic features, including several putative auxiliary protein-encoding genes, and capsid proteins with no sequence-level homology to those of other parvoviruses. Homology modeling indicates the absence of a β-A strand, normally part of the luminal side of the parvoviral capsid protein core. Our findings demonstrate that the ChPV lineage infects an exceptionally broad range of host species, including both vertebrates and invertebrates. Furthermore, we observe that ChPVs found in fish are more closely related to those from invertebrates than they are to those of amniote vertebrates. This suggests that transmission between distantly related host species may have occurred in the past and that the Parvoviridae family can no longer be divided based on host affiliation.

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Motley, W., S. Islam, K. Eagle, J. Bell, R. Sims, and M. Bowden. "Peroxisome Proliferator-Activated Receptor Gamma (PPARG) status defines the luminal lineage in molecular profiles of advanced urothelial cancers (UC)." European Journal of Cancer 174 (October 2022): S119. http://dx.doi.org/10.1016/s0959-8049(22)01117-0.

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50

Sphyris, Nathalie, Michael C. Hodder, and Owen J. Sansom. "Subversion of Niche-Signalling Pathways in Colorectal Cancer: What Makes and Breaks the Intestinal Stem Cell." Cancers 13, no. 5 (February 27, 2021): 1000. http://dx.doi.org/10.3390/cancers13051000.

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The intestinal epithelium fulfils pleiotropic functions in nutrient uptake, waste elimination, and immune surveillance while also forming a barrier against luminal toxins and gut-resident microbiota. Incessantly barraged by extraneous stresses, the intestine must continuously replenish its epithelial lining and regenerate the full gamut of specialized cell types that underpin its functions. Homeostatic remodelling is orchestrated by the intestinal stem cell (ISC) niche: a convergence of epithelial- and stromal-derived cues, which maintains ISCs in a multipotent state. Following demise of homeostatic ISCs post injury, plasticity is pervasive among multiple populations of reserve stem-like cells, lineage-committed progenitors, and/or fully differentiated cell types, all of which can contribute to regeneration and repair. Failure to restore the epithelial barrier risks seepage of toxic luminal contents, resulting in inflammation and likely predisposing to tumour formation. Here, we explore how homeostatic niche-signalling pathways are subverted in tumorigenesis, enabling ISCs to gain autonomy from niche restraints (“ISC emancipation”) and transform into cancer stem cells capable of driving tumour initiation, progression, and therapy resistance. We further consider the implications of the pervasive plasticity of the intestinal epithelium for the trajectory of colorectal cancer, the emergence of distinct molecular subtypes, the propensity to metastasize, and the development of effective therapeutic strategies.

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