Journal articles: 'Gastric organoid'

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Skubleny, Daniel, Saurabh Garg, Jim Wickware, Kieran Purich, Sunita Ghosh, Jennifer Spratlin, Dan Schiller, and Gina Rayat. "Murine and Human Gastric Tissue Establishes Organoids after 48 Hours of Cold Ischemia Time during Shipment." Biomedicines 11, no. 1 (January 6, 2023): 151. http://dx.doi.org/10.3390/biomedicines11010151.

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An inadequate supply of fresh tissue is a major limitation of three-dimensional patient-derived gastric organoid research. We propose that tissue procurement for organoid culture could be increased by developing a cold storage shipment protocol for fresh surgical tissues. Sixty stomach specimens from C57BL/6J mice were resected, of which forty-five were stored in Hank’s Balanced Salt (HBSS), University of Wisconsin (UW), or Histidine-Tryptophan-Ketoglutarate (HTK) solutions for subsequent organoid culture. Stomachs were dissociated and processed into gastric organoids as fresh tissue or after transport at 4 °C for 24 or 48 h. All gastric organoid cultures were established and maintained for 10 passages. Cold storage for 24 or 48 h did not significantly affect organoid viability. Although cold storage was associated with decreased organoid growth rate, there were no differences in viability, cytotoxic dose response, or LGR5 and TROY stem cell gene expression compared to organoids prepared from fresh tissue. As a proof of concept, six human gastric cancer organoids were established after 24 or 48 h of storage. Patient-derived gastric organoids from mouse and human gastric tissue can be established after 48 h of cold ischemia. Our method, which only requires ice packs, standard shipping containers, and HBSS is feasible and reliable. This method does not affect the reliability of downstream dose–response assays and maintains organoid viability for at least 10 passages. The shipment of fresh tissue for organoid procurement could serve to enhance multicenter collaboration and achieve more elaborate or controlled organoid experimentation.

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Seidlitz, Therese, Sebastian R. Merker, Alexander Rothe, Falk Zakrzewski, Cläre von Neubeck, Konrad Grützmann, Ulrich Sommer, et al. "Human gastric cancer modelling using organoids." Gut 68, no. 2 (April 27, 2018): 207–17. http://dx.doi.org/10.1136/gutjnl-2017-314549.

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ObjectiveGastric cancer is the second leading cause of cancer-related deaths and the fifth most common malignancy worldwide. In this study, human and mouse gastric cancer organoids were generated to model the disease and perform drug testing to delineate treatment strategies.DesignHuman gastric cancer organoid cultures were established, samples classified according to their molecular profile and their response to conventional chemotherapeutics tested. Targeted treatment was performed according to specific druggable mutations. Mouse gastric cancer organoid cultures were generated carrying molecular subtype-specific alterations.ResultsTwenty human gastric cancer organoid cultures were established and four selected for a comprehensive in-depth analysis. Organoids demonstrated divergent growth characteristics and morphologies. Immunohistochemistry showed similar characteristics to the corresponding primary tissue. A divergent response to 5-fluoruracil, oxaliplatin, irinotecan, epirubicin and docetaxel treatment was observed. Whole genome sequencing revealed a mutational spectrum that corresponded to the previously identified microsatellite instable, genomic stable and chromosomal instable subtypes of gastric cancer. The mutational landscape allowed targeted therapy with trastuzumab for ERBB2 alterations and palbociclib for CDKN2A loss. Mouse cancer organoids carrying Kras and Tp53 or Apc and Cdh1 mutations were characterised and serve as model system to study the signalling of induced pathways.ConclusionWe generated human and mouse gastric cancer organoids modelling typical characteristics and altered pathways of human gastric cancer. Successful interference with activated pathways demonstrates their potential usefulness as living biomarkers for therapy response testing.

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Caipa Garcia, Angela L., Jill E. Kucab, Halh Al-Serori, Rebekah S. S. Beck, Franziska Fischer, Matthias Hufnagel, Andrea Hartwig, et al. "Metabolic Activation of Benzo[a]pyrene by Human Tissue Organoid Cultures." International Journal of Molecular Sciences 24, no. 1 (December 29, 2022): 606. http://dx.doi.org/10.3390/ijms24010606.

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Organoids are 3D cultures that to some extent reproduce the structure, composition and function of the mammalian tissues from which they derive, thereby creating in vitro systems with more in vivo-like characteristics than 2D monocultures. Here, the ability of human organoids derived from normal gastric, pancreas, liver, colon and kidney tissues to metabolise the environmental carcinogen benzo[a]pyrene (BaP) was investigated. While organoids from the different tissues showed varied cytotoxic responses to BaP, with gastric and colon organoids being the most susceptible, the xenobiotic-metabolising enzyme (XME) genes, CYP1A1 and NQO1, were highly upregulated in all organoid types, with kidney organoids having the highest levels. Furthermore, the presence of two key metabolites, BaP-t-7,8-dihydrodiol and BaP-tetrol-l-1, was detected in all organoid types, confirming their ability to metabolise BaP. BaP bioactivation was confirmed both by the activation of the DNA damage response pathway (induction of p-p53, pCHK2, p21 and γ-H2AX) and by DNA adduct formation. Overall, pancreatic and undifferentiated liver organoids formed the highest levels of DNA adducts. Colon organoids had the lowest responses in DNA adduct and metabolite formation, as well as XME expression. Additionally, high-throughput RT-qPCR explored differences in gene expression between organoid types after BaP treatment. The results demonstrate the potential usefulness of organoids for studying environmental carcinogenesis and genetic toxicology.

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Jeong, Haengdueng, and Ki Taek Nam. "Gastric stem cell research and gastric organoids." Organoid 2 (December 6, 2022): e27. http://dx.doi.org/10.51335/organoid.2022.2.e27.

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The stomach is a complex organ lined with ordered epithelium consisting of different adult stem cell (ASC) pools. In the previous decade, research into gastric epithelial stem cells has been performed using lineage tracing methods, and several putative ASC markers in the gastric gland have been identified, although their roles in homeostasis maintenance and the origin of cancer remain to be clarified. With advances in gastric stem cell research, 3-dimensional (3D) organoid culture has been developed on the basis of in-depth insights into the control of stem cell self-renewal, proliferation, and differentiation. Since the initial report that single intestinal stem cells have the ability to generate long-lived 3D structures that exhibit budding forms and self-renewal, tissue-specific adaptations of this method have been established in various organs, such as the small intestine, colon, liver, and stomach. In the murine stomach, putative ASCs isolated from the corpus and antrum generate gastric organoids that can simulate organ-specific cells to some extent. In addition, a few trials have been conducted to generate long-lived 3D organoids using human-derived ASCs and pluripotent stem cells. We hope that this review will provide comprehensive knowledge on gastric stem cell research and gastric organoids.

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Hashimi, Marziah, Thomas A. Seberll, Barkan Sidar, James N. Wilking, and Diane Bimczok. "Epithelial cell-derived chemokines induce DC recruitment to the gastric epithelium upon H. pylori infection." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 51.6. http://dx.doi.org/10.4049/jimmunol.202.supp.51.6.

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Abstract H. pylori is a non-invasive bacterial pathogen that infects the lumen of the stomach and interacts with epithelial cells. In tissues from H. pylori infected and non-infected patients, DCs are found in close association with the gastric epithelium, which likely promotes DC uptake of luminal H. pylori. We hypothesized that DCs are recruited to the gastric epithelium in a chemokine-dependent manner. The aim of this study was to identify the epithelial chemokines that recruit DCs under steady state conditions and upon H. pylori infection. In chemotaxis assays, supernatants from human gastric organoids microinjected with H. pylori induced a 2-fold higher recruitment of monocyte-derived DCs compared to mock-infected organoids. Microscopic analysis of DC organoid-co-cultures similarly revealed DC recruitment to the epithelium of non-infected organoids and significantly increased recruitment upon H. pylori infection. DCs showed only low chemotactic activity towards H. pylori or bacterial supernatants, pointing to a role for epithelial rather than bacterial factors. DC migration towards the supernatants of both mock-infected and H. pylori-infected organoids was abrogated by pertussis toxin, indicating that recruitment was chemokine dependent. Using a chemokine array, we showed that organoid gastric organoids secreted increased amounts CXCL1, 5, 8 and CCL20 upon H. pylori infection, while CXCL16 and 17 remained constant. Chemotaxis assays confirmed that human DCs show chemotactic responses to CXCL1, 5, 8, 16, 17 and CCL20. In summary, our study indicates that human gastric epithelial cells actively recruit DCs to the mucosal interface by secreting chemokines, with increased recruitment induced upon H. pylori infection.

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Alexander, Katie L., Carolina A. Serrano, Asmi Chakraborty, Marie Nearing, Leona N. Council, Arnoldo Riquelme, Marcelo Garrido, Susan L. Bellis, Lesley E. Smythies, and Phillip D. Smith. "Modulation of glycosyltransferase ST6Gal-I in gastric cancer-derived organoids disrupts homeostatic epithelial cell turnover." Journal of Biological Chemistry 295, no. 41 (August 6, 2020): 14153–63. http://dx.doi.org/10.1074/jbc.ra120.014887.

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Programmed cell death promotes homeostatic cell turnover in the epithelium but is dysregulated in cancer. The glycosyltransferase ST6Gal-I is known to block homeostatic apoptosis through α2,6-linked sialylation of the death receptor TNFR1 in many cell types. However, its role has not been investigated in gastric epithelial cells or gastric tumorigenesis. We determined that human gastric antral epithelium rarely expressed ST6Gal-I, but the number of ST6Gal-I–expressing epithelial cells increased significantly with advancing premalignancy leading to cancer. The mRNA expression levels of ST6GAL-I and SOX9 in human gastric epithelial cells correlated positively with one another through the premalignancy cascade, indicating that increased epithelial cell expression of ST6Gal-I is associated with premalignant progression. To determine the functional impact of increased ST6Gal-I, we generated human gastric antral organoids from epithelial stem cells and differentiated epithelial monolayers from gastric organoids. Gastric epithelial stem cells strongly expressed ST6Gal-I, suggesting a novel biomarker of stemness. In contrast, organoid-derived epithelial monolayers expressed markedly reduced ST6Gal-I and underwent TNF-induced, caspase-mediated apoptosis, consistent with homeostasis. Conversely, epithelial monolayers generated from gastric cancer stem cells retained high levels of ST6Gal-I and resisted TNF-induced apoptosis, supporting prolonged survival. Protection from TNF-induced apoptosis depended on ST6Gal-I overexpression, because forced ST6Gal-I overexpression in normal gastric stem cell–differentiated monolayers inhibited TNF-induced apoptosis, and cleavage of α2,6-linked sialic acids from gastric cancer organoid-derived monolayers restored susceptibility to TNF-induced apoptosis. These findings implicate up-regulated ST6Gal-I expression in blocking homeostatic epithelial cell apoptosis in gastric cancer pathogenesis, suggesting a mechanism for prolonged epithelioid tumor cell survival.

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Li, Haixin, Hongkun Liu, and Kexin Chen. "Living biobank-based cancer organoids: prospects and challenges in cancer research." Cancer Biology & Medicine 19, no. 7 (July 21, 2022): 965–82. http://dx.doi.org/10.20892/j.issn.2095-3941.2021.0621.

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Biobanks bridge the gap between basic and translational research. Traditional cancer biobanks typically contain normal and tumor tissues, and matched blood. However, biospecimens in traditional biobanks are usually nonrenewable. In recent years, increased interest has focused on establishing living biobanks, including organoid biobanks, for the collection and storage of viable and functional tissues for long periods of time. The organoid model is based on a 3D in vitro cell culture system, is highly similar to primary tissues and organs in vivo, and can recapitulate the phenotypic and genetic characteristics of target organs. Publications on cancer organoids have recently increased, and many types of cancer organoids have been used for modeling cancer processes, as well as for drug discovery and screening. On the basis of the current research status, more exploration of cancer organoids through technical advancements is required to improve reproducibility and scalability. Moreover, given the natural characteristics of organoids, greater attention must be paid to ethical considerations. Here, we summarize recent advances in cancer organoid biobanking research, encompassing rectal, gastric, pancreatic, breast, and glioblastoma cancers. Living cancer biobanks that contain cancerous tissues and matched organoids with different genetic backgrounds, subtypes, and individualized characteristics will eventually contribute to the understanding of cancer and ultimately facilitate the development of innovative treatments.

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Chen, Wei, Jian Zhang, Huafeng Fu, Xun Hou, Qiao Su, Yulong He, and Dongjie Yang. "KLF5 Is Activated by Gene Amplification in Gastric Cancer and Is Essential for Gastric Cell Proliferation." Cells 10, no. 5 (April 24, 2021): 1002. http://dx.doi.org/10.3390/cells10051002.

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Gastric cancer is the third leading cause of cancer death worldwide. In this study, we tried to clarify the function of KLF5 in gastric cancer. Copy number variation (CNV) and the expression of KLF5 were interrogated in public datasets. The clinical significance of KLF5 amplification and gene expression in gastric cancer were evaluated. The function of KLF5 in cell proliferation was studied in gastric cancer cell lines and organoids. We found that KLF5 amplification mainly occurred in the chromosome instable tumors (CIN) and was significantly associated with TP53 mutation. In addition, higher KLF5 expression correlated with more locally invasive gastric cancer and higher T stage. Next, a KLF5 gene expression signature was curated. The genes in the signature were involved in cell development, cell cycle regulation, cell death, suggesting potential roles played by KLF5. Functional studies using siRNAs revealed that KLF5 was essential for the proliferation of gastric cancer cells. Finally, using gastric organoid models, we revealed that the proliferation of organoids was significantly inhibited after the down regulation of KLF5. Our study revealed that KLF5 was amplified and over-expressed in gastric cancer, and it may play an oncogene-like role in gastric cancer by supporting cell proliferation.

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Seidlitz, Therese, and Daniel E. Stange. "Gastrointestinal cancer organoids—applications in basic and translational cancer research." Experimental & Molecular Medicine 53, no. 10 (October 2021): 1459–70. http://dx.doi.org/10.1038/s12276-021-00654-3.

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AbstractCancer is a major health problem and a leading cause of death worldwide. Early cancer detection and continuous changes in treatment strategies have improved overall patient survival. The recent development of targeted drugs offers new opportunities for personalized cancer treatment. Nevertheless, individualized treatment is accompanied by the need for biomarkers predicting the response of a patient to a certain drug. One of the most promising breakthroughs in recent years that might help to overcome this problem is the organoid technology. Organoid cultures exhibit self-renewal capacity, self-organization, and long-term proliferation, while recapitulating many aspects of their primary tissue. Generated patient-derived organoid (PDO) libraries constitute “living” biobanks, allowing the in-depth analysis of tissue function, development, tumor initiation, and cancer pathobiology. Organoids can be derived from all gastrointestinal tissues, including esophageal, gastric, liver, pancreatic, small intestinal and colorectal tissues, and cancers of these tissues. PDOs are amenable to various techniques, including sequencing analyses, drug screening, targeted therapy testing, tumor microenvironment studies, and genetic engineering capabilities. In this review, we discuss the different applications of gastrointestinal organoids in basic cancer biology and clinical translation.

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Idowu, Sulaimon, Paul P. Bertrand, and Anna K. Walduck. "Homeostasis and Cancer Initiation: Organoids as Models to Study the Initiation of Gastric Cancer." International Journal of Molecular Sciences 23, no. 5 (March 3, 2022): 2790. http://dx.doi.org/10.3390/ijms23052790.

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Gastric cancer represents a significant disease burden worldwide. The factors that initiate cancer are not well understood. Chronic inflammation such as that triggered by H. pylori infection is the most significant cause of gastric cancer. In recent years, organoid cultures developed from human and animal adult stem cells have facilitated great advances in our understanding of gastric homeostasis. Organoid models are now being exploited to investigate the role of host genetics and bacterial factors on proliferation and DNA damage in gastric stem cells. The impact of a chronic inflammatory state on gastric stem cells and the stroma has been less well addressed. This review discusses what we have learned from the use of organoid models to investigate cancer initiation, and highlights questions on the contribution of the microbiota, chronic inflammatory milieu, and stromal cells that can now be addressed by more complex coculture models.

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Bougen-Zhukov, Nicola, Lyvianne Decourtye-Espiard, Wilson Mitchell, Kieran Redpath, Jacqui Perkinson, Tanis Godwin, Michael A. Black, and Parry Guilford. "E-Cadherin-Deficient Cells Are Sensitive to the Multikinase Inhibitor Dasatinib." Cancers 14, no. 7 (March 22, 2022): 1609. http://dx.doi.org/10.3390/cancers14071609.

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The CDH1 gene, encoding the cell adhesion protein E-cadherin, is one of the most frequently mutated genes in gastric cancer and inactivating germline CDH1 mutations are responsible for the cancer syndrome hereditary diffuse gastric cancer (HDGC). CDH1-deficient gastric cancers exhibit high AKT serine/threonine kinase 3 (AKT3) expression, but specific drugs against this AKT isoform are not available. We therefore used two publicly available datasets to identify AKT3-associated genes which could be used to indirectly target AKT3. Reactome analysis identified an enrichment of extracellular matrix remodelling genes in AKT3-high gastric cancers. Of the 51 genes that were significantly correlated with AKT3 (but not AKT1), discoidin domain receptor tyrosine kinase 2 (DDR2) showed the strongest positive association. Treatment of isogenic human cells and mouse gastric and mammary organoids with dasatinib, a small molecule inhibitor of multiple kinases including SRC, BCR-ABL and DDR2, preferentially slowed the growth and induced apoptosis of E-cadherin-deficient cells. Dasatinib treatment also preferentially slowed the growth of gastric and mammary organoids harbouring both Cdh1 and Tp53 mutations. In organoid models, dasatinib treatment was associated with decreased phosphorylation of total AKT, with a stronger effect seen in Cdh1-deficient organoids. Treatment with combinations of dasatinib and an inhibitor of AKT, MK2206, enhanced the effect of dasatinib in breast MCF10A cells. In conclusion, targeting the DDR2-SRC-AKT3 axis with dasatinib represents a promising approach for the chemoprevention and chemotherapy of gastric and breast cancers lacking E-cadherin.

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Hashimi, Marziah, Julia Schearer, Thomas Sebrell, Andrew B. Gentry, and Diane Bimczok. "Helicobacter pylori infected gastric epithelial cells drive dendritic cells towards a tolerogenic phenotype." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 65.12. http://dx.doi.org/10.4049/jimmunol.206.supp.65.12.

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Abstract The interactions of dendritic cells (DCs) with the gastric epithelium are thought to play a role in shaping DC function and thus the adaptive immune response to Helicobacter pylori (H. pylori) infection. We have shown that DCs are recruited to the H. pylori-infected gastric epithelium, positioning them for uptake of bacterial antigen from the gastric lumen. Using a gastric organoid model of H. pylori infection, we sought to define how the interactions between gastric epithelial cells and DCs regulate the antigen-presenting cell capacity of DCs. Supernatants were collected from organoids microinjected with H. pylori (infected) or PBS (mock), and monocyte-derived dendritic cells (MoDCs) were incubated with these supernatants. Flow cytometry data showed that the supernatant from infected organoids drove the DCs toward a tolerogenic state, as the expression of CD40, CD83, and CD86 was significantly decreased compared to incubation with supernatants from mock infected organoids, whereas CCR7 expression was increased consistent with a more tolerogenic phenotype. DCs treated with supernatants from infected, but not mock-infected organoids suppressed the proliferation of naïve autologous T cells. We also assessed T cell polarization using a cytokine array and found an increase in Th1, Th17 and Treg cytokines, but a decrease in Th2 cytokines in T cells that were challenged with DCs pre-treated with supernatants from infected organoids compared to mock-infected organoids. In summary, we have shown that H. pylori-infected gastric epithelium drives the DCs toward a tolerogenic state, resulting in reduced expression of maturation markers and CD4+ T cell proliferation while maintaining the DCs’ ability to induce T cell cytokine secretion.

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Thomas, Hugh. "Exploring human gastric cancers through organoid culture." Nature Reviews Gastroenterology & Hepatology 15, no. 10 (September 7, 2018): 581. http://dx.doi.org/10.1038/s41575-018-0066-x.

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Sayols, Sergi, Jakub Klassek, Clara Werner, Stefanie Möckel, Sandra Ritz, Maria Mendez-Lago, and Natalia Soshnikova. "Signalling codes for the maintenance and lineage commitment of embryonic gastric epithelial progenitors." Development 147, no. 18 (September 2, 2020): dev188839. http://dx.doi.org/10.1242/dev.188839.

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ABSTRACTThe identity of embryonic gastric epithelial progenitors is unknown. We used single-cell RNA-sequencing, genetic lineage tracing and organoid assays to assess whether Axin2- and Lgr5-expressing cells are gastric progenitors in the developing mouse stomach. We show that Axin2+ cells represent a transient population of embryonic epithelial cells in the forestomach. Lgr5+ cells generate both glandular corpus and squamous forestomach organoids ex vivo. Only Lgr5+ progenitors give rise to zymogenic cells in culture. Modulating the activity of the WNT, BMP and Notch pathways in vivo and ex vivo, we found that WNTs are essential for the maintenance of Lgr5+ epithelial cells. Notch prevents differentiation of the embryonic epithelial cells along all secretory lineages and hence ensures their maintenance. Whereas WNTs promote differentiation of the embryonic progenitors along the zymogenic cell lineage, BMPs enhance their differentiation along the parietal lineage. In contrast, WNTs and BMPs are required to suppress differentiation of embryonic gastric epithelium along the pit cell lineage. Thus, coordinated action of the WNT, BMP and Notch pathways controls cell fate determination in the embryonic gastric epithelium.

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Fujimori, Yoshifumi, Taiji Akamatsu, Hiroyoshi Ota, and Tsutomu Katsuyama. "Proliferative markers in gastric carcinoma and organoid differentiation." Human Pathology 26, no. 7 (July 1995): 725–34. http://dx.doi.org/10.1016/0046-8177(95)90219-8.

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Eissmann, Moritz, Anne Huber, Amr Allam, Christine Dijkstra, and Matthias Ernst. "Abstract 252: STAT3 signaling in the tumor microenvironment promotes primary gastric cancer growth and metastasis formation." Cancer Research 82, no. 12_Supplement (June 15, 2022): 252. http://dx.doi.org/10.1158/1538-7445.am2022-252.

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Abstract Tumor cell intrinsic activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling has been shown to promote stemness, tumorigenesis and cancer therapy resistance. Therefore, Stat3 inhibitors are being developed and tested pre-clinically and in clinical trials for multiple solid cancers. Importantly, STAT3 signaling also occurs in the non-tumor cells within the tumor microenvironment (TME). The effect of Stat3 signaling within the TME on primary gastric cancers (GC), metastasis formation and therapy responses is unknown. Here, we describe a novel genetically defined, tumor organoid-driven, transplantable, orthotopic gastric cancer model that represents gastric carcinomas with associated metastasis formation in immune competent recipient mice. Utilizing our murine GC organoid model in subcutaneous allograft experiments, we showed that established GC tumors respond to pharmacological Stat3 inhibition. This anti-tumor effect is primarily driven by inhibition of the Stat3 signaling in the TME as tumor growth was increased in Stat3 high TME recipients, while tumor growth was inhibited in Stat3-signaling reduced Stat3+/- mice. Furthermore, Crisp-Cas9 -mediated Stat3 knockout in the GC organoids did not alter their in vitro growth potential. Stat3KO GC allograft tumor growth was not changed compared to Stat3WT GC tumors grown in wildtype host mice. Collectively, this suggests that inhibition of Stat3 signaling within the TME but not the tumor cell intrinsic Stat3 reduction confer anti-tumor responses. Through gastric serosa transplantation of the murine GC organoids into Stat3-elevated gp130FF mutant mice, we confirmed that high Stat3 signaling within the TME promotes distal metastasis formation to the liver. Taken together, we show that Stat3 signaling represents a therapy target, that predominantly acts through the TME. Better understanding of the signaling within the TME in primary and metastatic GC lesions will allow identification of novel tumor cell and TME-centric therapy targets. Combination of therapies targeting tumor cell intrinsic vulnerabilities with novel pro-tumorigenic TME -targeting agents could help to improve responses against primary and metastatic disease and therefore improve outcome for the worst prognosis patients. Citation Format: Moritz Eissmann, Anne Huber, Amr Allam, Christine Dijkstra, Matthias Ernst. STAT3 signaling in the tumor microenvironment promotes primary gastric cancer growth and metastasis formation [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 252.

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Arana, Alexa Morales, Nicole B. Halmai, Hongyong Zhang, Paul Lott, Ana Estrada-Florez, Ted W. Toal, and Luis G. Carvajal-Carmona. "Abstract 3066: Functional modeling and characterization of high frequency mutations associated with gastric cancer in US racial and ethnic minority populations." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3066. http://dx.doi.org/10.1158/1538-7445.am2022-3066.

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Abstract Gastric cancer (GC) is the 5th most common neoplasm and the 2nd most deadly cancer worldwide, with an estimated 783,000 deaths in 2018. Furthermore, Hispanic/Latino Americans continue to be underrepresented in GC genomic studies despite being twice as likely to be diagnosed with and die from GC compared to non-Hispanic whites (NHW). In order to address this pervasive health disparity, our lab has led efforts to characterize tumor biopsies from racial/ethnic minority cancer patients to inform more effective cancer treatment and advance precision medicine among these high-risk populations. We performed whole-exome sequencing of 31 GC patient tumors with more than 60% of the samples coming from minority patients. We identified higher somatic mutation frequencies in the ARID1A, BRCA2, and APC genes compared with the TCGA GC cohort, which is made up of mostly NHW patients. To better understand the role these genes play in cancer tumorigenesis among racial/ethnic minority GC patients, our lab has established a CRISPR/Cas9 genome-editing platform in minority patient-derived organoids (mPDOs). In this study, we utilized our platform to generate mPDO models of APC-TP53 double knockouts (dKO), ARID1A-TP53 dKO, and TP53-ARID1A-BRCA2 triple knockouts in organoid lines derived from normal gastric tissue. We developed medium to select for functional mutants following organoid cell electroporation that yielded near-complete selection for the desired gene knockouts, allowing us to generate isogenic mPDO lines modeling each gene KO combination. Our organoid models will provide a critical method to elucidate therapeutic sensitivity and resistance mechanisms in minority groups towards the ultimate goal of addressing GC health disparities in US racial/ethnic minorities. Citation Format: Alexa Morales Arana, Nicole B. Halmai, Hongyong Zhang, Paul Lott, Ana Estrada-Florez, Ted W. Toal, University of California Minority Patient-DerivedXenograft (PDX) Development and Trial (UCaMP) Cent, Luis G. Carvajal-Carmona. Functional modeling and characterization of high frequency mutations associated with gastric cancer in US racial and ethnic minority populations [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 3066.

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Murakami, Kazuhiro, Yumi Terakado, Kikue Saito, Yoshie Jomen, Haruna Takeda, Masanobu Oshima, and Nick Barker. "A genome-scale CRISPR screen reveals factors regulating Wnt-dependent renewal of mouse gastric epithelial cells." Proceedings of the National Academy of Sciences 118, no. 4 (January 21, 2021): e2016806118. http://dx.doi.org/10.1073/pnas.2016806118.

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An ability to safely harness the powerful regenerative potential of adult stem cells for clinical applications is critically dependent on a comprehensive understanding of the underlying mechanisms regulating their activity. Epithelial organoid cultures accurately recapitulate many features of in vivo stem cell-driven epithelial renewal, providing an excellent ex vivo platform for interrogation of key regulatory mechanisms. Here, we employed a genome-scale clustered, regularly interspaced, short palindromic repeats (CRISPR) knockout (KO) screening assay using mouse gastric epithelial organoids to identify modulators of Wnt-driven stem cell-dependent epithelial renewal in the gastric mucosa. In addition to known Wnt pathway regulators, such as Apc, we found that KO of Alk, Bclaf3, or Prkra supports the Wnt independent self-renewal of gastric epithelial cells ex vivo. In adult mice, expression of these factors is predominantly restricted to non-Lgr5–expressing stem cell zones above the gland base, implicating a critical role for these factors in suppressing self-renewal or promoting differentiation of gastric epithelia. Notably, we found that Alk inhibits Wnt signaling by phosphorylating the tyrosine of Gsk3β, while Bclaf3 and Prkra suppress regenerating islet-derived (Reg) genes by regulating the expression of epithelial interleukins. Therefore, Alk, Bclaf3, and Prkra may suppress stemness/proliferation and function as novel regulators of gastric epithelial differentiation.

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Huber, Anne, Christine Dijkstra, Vicki Whitehall, Matthias Ernst, and Moritz Eissmann. "Abstract A49: Proof of principle that loss of mismatch repair protein reduces tumor burden in mouse model of gastric cancer." Cancer Immunology Research 10, no. 12_Supplement (December 1, 2022): A49. http://dx.doi.org/10.1158/2326-6074.tumimm22-a49.

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Abstract Gastric cancer (GC) remains the third leading cause of cancer-related death worldwide. Unfortunately, only a subset of GC patients, characterized by tumors with high microsatellite instability (MSI), responds to immune checkpoint (ICI) therapy. In the context of GC, the mechanisms of how MSI improves ICI therapy responses remain poorly understood. Here we are undertaking a proof of principle study to demonstrate in novel GC mouse models that loss of mismatch repair protein MLH1 confers MSI phenotype and impairs tumor growth via altered anti-tumor immune responses. To study the functional and mechanistic effects of loss of MLH1 protein, we established MLH1-deficient (Kras-, Pi3kca-, Tp53-mutant) murine tumor organoids via CRISPR/Cas9 technology. These organoids were subcutaneously allografted into immunocompetent C57BL/6 mice to study tumor progression, immune surveillance, and responses to immunotherapy in vivo. MSI testing confirmed that MLH1-proficient parental organoids are MSI low, whereas MLH1-deficient organoids are MSI high. Low passage MLH1-deficient organoid tumors grew similarly to MLH1-proficient tumors. However, after culturing of organoids in vitro for a prolonged time prior to injection to allow accumulation of mutations, subcutaneous allograft MLH1-deficient tumors were considerably smaller compared to MLH1-proficient tumors. MLH1-deficient tumors showed a significantly higher number of CD8+ T cells. Additionally, MLH1-deficient tumors were similar in size to MLH1-proficient tumors when allografted into Rag1-/- mice. Interestingly, CD8- and CD4-depleting experiments showed an involvement of CD4+ T cells in the impairment of MLH1-deficient tumor growth. Treatment with anti-PD-1, but not anti-CTLA-4, reduced tumor mass further. We are currently investigating the underlying mechanism for the impaired growth of MLH1-deficient organoid allograft tumors via tumor mutational burden analysis and neoantigen testing. Taken together, we provide evidence that loss of MLH1 leads to high MSI in gastric tumors, reduces tumor growth after prolonged in vitro culture and increases response to anti-PD-1 therapy. Our findings encourage further studies to investigate the mechanisms of impaired tumor growth after MLH1 loss in GC and may provide insights leading to improve ICI therapy responses for GC patients. Citation Format: Anne Huber, Christine Dijkstra, Vicki Whitehall, Matthias Ernst, Moritz Eissmann. Proof of principle that loss of mismatch repair protein reduces tumor burden in mouse model of gastric cancer [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 A49.

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Perabo, Frank, Chandtip Chandhasin, Sanghee Yoo, Van Dang, Joselyn Del Rosario, Young K. Chen, Jeffrey Stafford, Stephen Quake, and Michael F. Clarke. "TACH101, a first-in-class pan-inhibitor of KDM4 for treatment of gastrointestinal cancers." Journal of Clinical Oncology 40, no. 4_suppl (February 1, 2022): 132. http://dx.doi.org/10.1200/jco.2022.40.4_suppl.132.

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132 Background: TACH101 is a novel, potent small molecule inhibitor of KDM4, a novel epigenetic target for cancer therapy. KDM4 is a family of histone lysine demethylases that, when overexpressed, drives key processes linked to cancer. Validation of KDM4 as a driver gene was confirmed across gastrointestinal tumor types including esophageal, colon and gastric cancers, and is associated with formation of aggressive tumors. Methods: TACH101 was evaluated in in vitro and in vivo studies including cell inhibition assays, patient-derived xenograft (PDX) and organoid models, and bioinformatics analyses studies. Results: In vitro, TACH101 treatment potently inhibited cell proliferation in cell lines and organoid models representing esophageal, CRC, and gastric cancers. TACH101 induced apoptosis in human CRC (HT-29) and esophageal (KYSE-150) cancer cell lines (EC50s 0.033 - 0.092 µM). Further evaluation using a panel of > 300 cell lines from different tumor types showed potent activity of TACH101 against gastric cancer and CRC. In gastric cancer, 2D cell viability inhibition assays conducted on a panel of 11 gastric cancer cell lines showed 9/11 (82%) were sensitive to TACH101 treatment (IC50 0.004 - 0.072 µM); in PDX models, 4/5 (80%) were sensitive to TACH101 treatment (IC50 0.007 - 0.039 µM). In CRC, bioinformatics analysis indicated increased TACH101 sensitivity in cell lines with MSI-H status (IC50 1-150 nM). Sensitivity of MSI-H CRC to TACH101 was further confirmed in a panel of 14 CRC PDX models and 7 CRC organoid models in culture-based viability inhibition assays. In PDX models, 5/5 (100%) characterized as MSI were sensitive to TACH101 treatment (IC50 0.001 - 0.014 µM), whereas 4/8 (50%) characterized as MSS were sensitive to TACH101 (IC50 0.003 - 0.270 µM). In patient derived CRC organoid models, 3/3 (100%) characterized as MSI were sensitive to TACH101 treatment (IC50 0.022 - 0.149 µM) whereas 0/3 (0%) characterized as MSS were sensitive (IC50 > 10 µM). In vivo, TACH101 triggered effective tumor control (≥70%) in xenograft models of CRC (SU60), esophageal (KYSE-150) and gastric (GXA-3036) cancers. Pharmacologic studies showed TACH101 demonstrated favorable cell permeability, good oral bioavailability, and high metabolic stability. Conclusions: Preclinical work on TACH101 KDM4 inhibitor demonstrates compelling data and applicability as a potential therapy for gastrointestinal cancers. Preparations to advance TACH101 into clinical trials are underway.

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Steele, Nina G., Jayati Chakrabarti, Jiang Wang, Jacek Biesiada, Loryn Holokai, Julie Chang, Lauren M. Nowacki, et al. "An Organoid-Based Preclinical Model of Human Gastric Cancer." Cellular and Molecular Gastroenterology and Hepatology 7, no. 1 (2019): 161–84. http://dx.doi.org/10.1016/j.jcmgh.2018.09.008.

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Singh, Harshabad, Davide Seruggia, Shariq Madha, Madhurima Saxena, Ankur K. Nagaraja, Zhong Wu, Jin Zhou, et al. "Transcription factor-mediated intestinal metaplasia and the role of a shadow enhancer." Genes & Development 36, no. 1-2 (December 30, 2021): 38–52. http://dx.doi.org/10.1101/gad.348983.121.

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Barrett's esophagus (BE) and gastric intestinal metaplasia are related premalignant conditions in which areas of human stomach epithelium express mixed gastric and intestinal features. Intestinal transcription factors (TFs) are expressed in both conditions, with unclear causal roles and cis-regulatory mechanisms. Ectopic CDX2 reprogrammed isogenic mouse stomach organoid lines to a hybrid stomach–intestinal state transcriptionally similar to clinical metaplasia; squamous esophageal organoids resisted this CDX2-mediated effect. Reprogramming was associated with induced activity at thousands of previously inaccessible intestine-restricted enhancers, where CDX2 occupied DNA directly. HNF4A, a TF recently implicated in BE pathogenesis, induced weaker intestinalization by binding a novel shadow Cdx2 enhancer and hence activating Cdx2 expression. CRISPR/Cas9-mediated germline deletion of that cis-element demonstrated its requirement in Cdx2 induction and in the resulting activation of intestinal genes in stomach cells. dCas9-conjugated KRAB repression mapped this activity to the shadow enhancer's HNF4A binding site. Altogether, we show extensive but selective recruitment of intestinal enhancers by CDX2 in gastric cells and that HNF4A-mediated ectopic CDX2 expression in the stomach occurs through a conserved shadow cis-element. These findings identify mechanisms for TF-driven intestinal metaplasia and a likely pathogenic TF hierarchy.

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Ku, Chia-Chen, Kenly Wuputra, Jia-Bin Pan, Chia-Pei Li, Chung-Jung Liu, Yi-Chang Liu, Shigeo Saito, et al. "Generation of Human Stomach Cancer iPSC-Derived Organoids Induced by Helicobacter pylori Infection and Their Application to Gastric Cancer Research." Cells 11, no. 2 (January 6, 2022): 184. http://dx.doi.org/10.3390/cells11020184.

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There is considerable cellular diversity in the human stomach, which has helped to clarify cell plasticity in normal development and tumorigenesis. Thus, the stomach is an interesting model for understanding cellular plasticity and for developing prospective anticancer therapeutic agents. However, many questions remain regarding the development of cancers in vivo and in vitro in two- or three-dimensional (2D/3D) cultures, as well as the role of Helicobacter pylori (H. p.) infection. Here, we focus on the characteristics of cancer stem cells and their derived 3D organoids in culture, including the formation of stem cell niches. We define the conditions required for such organoid culture in vitro and examine the ability of such models for testing the use of anticancer agents. We also summarize the signaling cascades and the specific markers of stomach-cancer-derived organoids induced by H. p. infection, and their stem cell niches.

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Hirshorn, Sabrina T., Nina Steele, and Yana Zavros. "Modeling pancreatic pathophysiology using genome editing of adult stem cell-derived and induced pluripotent stem cell (iPSC)-derived organoids." American Journal of Physiology-Gastrointestinal and Liver Physiology 320, no. 6 (June 1, 2021): G1142—G1150. http://dx.doi.org/10.1152/ajpgi.00329.2020.

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The goal of this review is not only to provide highlights on the development of organoid technology but also to subsequently use this information to study the pathophysiology of those specific mutations in the formation of malignant pancreatic and gastric cancer.

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Harada, Kenji, Naoya Sakamoto, Shoichi Ukai, Tsuyoshi Takashima, Ryota Maruyama, Daiki Taniyama, Kazuaki Tanabe, Hideki Ohdan, and Wataru Yasui. "Abstract 6186: Identification of MYOF as a novel biomarker by using oxaliplatin-resistant gastric cancer organoid model." Cancer Research 82, no. 12_Supplement (June 15, 2022): 6186. http://dx.doi.org/10.1158/1538-7445.am2022-6186.

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Abstract Background: The prognosis of gastric cancer (GC) is improving due to the development of chemotherapy, however, intrinsic or acquired resistance to anti-cancer drugs is still a major clinical challenge. Oxaliplatin (L-OHP) is one of the anti-cancer drugs used as first-line treatment for GC. As with other anti-cancer drugs, although acquired resistance to L-OHP is a major problem, no biomarkers are clinically available for L-OHP response. Recently, cancer stem cells (CSCs) were shown to be involved in the acquisition of drug resistance. Hence, the major goal is to discover novel predictive biomarkers and overcome L-OHP resistance in GC in relation to CSCs. Methods: We used the organoid model; a culture method that allows 3D in vitro culturing of tissue-like structures and is presumed to contain many stem/progenitor cells. We established three independent L-OHP-resistant gastric cancer organoids (GCOs) by adding increasing doses of L-OHP in the culture medium over time. Gene expression profiles of the pairs of parental and resistant organoids were evaluated using microarray analysis. We analyzed the microarray data of L-OHP-resistant GCOs with our previous study from 5-fluorouracil (5-FU)-resistant GCOs (GSE154127). We validated the upregulated genes in the L-OHP-resistant GCOs by qRT-PCR. To confirm the use of upregulated genes as a novel biomarker, we immunohistochemically evaluated the expression levels in GC tissue samples. Furthermore, we analyzed the effects of knockdown using both GC cell lines and GCOs. Results: Through the comparison of the data, we detected myoferlin (MYOF) to be a candidate gene responsible only for L-OHP resistance. qRT-PCR results confirmed the results of the microarray and found that high expression of MYOF correlated significantly with the IC50 of L-OHP in GCOs. Immunohistochemistry analysis for MYOF using 132 GC cases showed that high expression of MYOF was significantly associated with poor prognosis, T grade, N grade, and lymphatic invasion, and showed MYOF to be an independent prognostic indicator, especially in the GC patients treated with platinum-based chemotherapy. The knockdown or inhibition of MYOF by WJ460 in GC cell line and GCOs enhanced L-OHP sensitivity while it reduced cell growth, spheroid/organoid formation, migration, invasion, and in vivo tumorigenesis. Conclusion: We highlight that MYOF is highly involved in L-OHP resistance and tumor progression in GC. Our results indicate that MYOF could be a promising biomarker in GC to predict L-OHP sensitivity and tumor progression and a potential candidate gene as a therapeutic target. Citation Format: Kenji Harada, Naoya Sakamoto, Shoichi Ukai, Tsuyoshi Takashima, Ryota Maruyama, Daiki Taniyama, Kazuaki Tanabe, Hideki Ohdan, Wataru Yasui. Identification of MYOF as a novel biomarker by using oxaliplatin-resistant gastric cancer organoid model [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 6186.

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Hakuno, Sarah K., Ellis Michiels, Eleonore B. Kuhlemaijer, Ilse Rooman, Lukas J. A. C. Hawinkels, and Marije Slingerland. "Multicellular Modelling of Difficult-to-Treat Gastrointestinal Cancers: Current Possibilities and Challenges." International Journal of Molecular Sciences 23, no. 6 (March 15, 2022): 3147. http://dx.doi.org/10.3390/ijms23063147.

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Cancers affecting the gastrointestinal system are highly prevalent and their incidence is still increasing. Among them, gastric and pancreatic cancers have a dismal prognosis (survival of 5–20%) and are defined as difficult-to-treat cancers. This reflects the urge for novel therapeutic targets and aims for personalised therapies. As a prerequisite for identifying targets and test therapeutic interventions, the development of well-established, translational and reliable preclinical research models is instrumental. This review discusses the development, advantages and limitations of both patient-derived organoids (PDO) and patient-derived xenografts (PDX) for gastric and pancreatic ductal adenocarcinoma (PDAC). First and next generation multicellular PDO/PDX models are believed to faithfully generate a patient-specific avatar in a preclinical setting, opening novel therapeutic directions for these difficult-to-treat cancers. Excitingly, future opportunities such as PDO co-cultures with immune or stromal cells, organoid-on-a-chip models and humanised PDXs are the basis of a completely new area, offering close-to-human models. These tools can be exploited to understand cancer heterogeneity, which is indispensable to pave the way towards more tumour-specific therapies and, with that, better survival for patients.

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Chakrabarti, Jayati, Vivien Koh, Nina Steele, Jennifer Hawkins, Yoshiaki Ito, Juanita L. Merchant, Jiang Wang, et al. "Disruption of Her2-Induced PD-L1 Inhibits Tumor Cell Immune Evasion in Patient-Derived Gastric Cancer Organoids." Cancers 13, no. 24 (December 7, 2021): 6158. http://dx.doi.org/10.3390/cancers13246158.

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(1) Background: The expression of programmed death-ligand 1 (PD-L1), which interacts with programmed cell death protein 1 (PD-1) on cytotoxic T lymphocytes (CTLs), enables tumors to escape immunosurveillance. The PD-1/PD-L1 interaction results in the inhibition of CTL proliferation, and effector function, thus promoting tumor cell evasion from immunosurveillance and cancer persistence. Despite 40% of gastric cancer patients exhibiting PD-L1 expression, only a small subset of patients responds to immunotherapy. Human epidermal growth factor receptor2 (HER2) is one of the critical regulators of several solid tumors, including metastatic gastric cancer. Although half of PD-L1-positive gastric tumors co-express HER2, crosstalk between HER2 and PD-1/PD-L1 in gastric cancer remains undetermined. (2) Methods: Human gastric cancer organoids (huTGOs) were generated from biopsied or resected tissues and co-cultured with CTLs and myeloid-derived suppressor cells (MDSCs). Digital Spatial Profiling (DSP) was performed on FFPE tissue microarrays of numerous gastric cancer patients to examine the protein expression of immune markers. (3) Results: Knockdown of HER2 in PD-L1/HER2-positive huTGOs led to a concomitant decrease in PD-L1 expression. Similarly, in huTGOs/immune cell co-cultures, PD-L1 expression decreased in huTGOs and was correlated with an increase in CTL proliferation which enhanced huTGO death. Treatment with Nivolumab exhibited similar effects. However, a combinatorial treatment with Mubritinib and Nivolumab was unable to inhibit HER2 expression in co-cultures containing MDSCs. (4) Conclusions: Our study suggested that co-expression of HER2 and PD-L1 may contribute to tumor cell immune evasion. In addition, autologous organoid/immune cell co-cultures can be exploited to effectively screen responses to a combination of anti-HER2 and immunotherapy to tailor treatment for gastric cancer patients.

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Hoffman, Adam, Sanjima Pal, Veena Sangwan, and Lorenzo Ferri. "Abstract 2625: Personalized chemotherapy treatments for microsatellite instable tumors." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2625. http://dx.doi.org/10.1158/1538-7445.am2022-2625.

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Abstract Introduction: Esophagogastric adenocarcinomas with microsatellite instability (MSI) high status often display chemoresistance, as the current therapies are ineffective. It is hypothesized that the poor response of MSI-high esophagogastric adenocarcinomas to therapies is due to the extensive genomic mutational heterogeneity, which can be overcome by identifying, stratifying, and targeting multiple genetic alterations concurrently. The goals of this project are to: 1) Identify a matched retrospective cohort of 20 MSI-high to 20 microsatellite stable organoids, derived from biobanked tumor tissue. 2) Analyze mismatch repair protein function/loss, to confirm that the primary tumor microsatellite status is recapitulated in 3D organoid models. 3) Test standard of care chemotherapies, and explore alternative approaches to prevent chemoresistance by evaluating targeted agents based on genomic sequencing. Methods: Patient-derived organoids grow for ~14 days, after which they are enzymatically disrupted and plated in Matrigel. I will confirm that the organoid models accurately represent clinal response, by treating them with the same chemotherapy received by the patient. 10 different drug concentrations are added in triplicate using a drug dispenser, then after 72 hours, organoid viability is determined with a plate reader. Results: Genomic characterization of 13/226 MSI-high cases has been conducted with a 234 gene gastric cancer specific panel to identify and target genomic alterations. Preliminary robotic drug screens guided by these mutation profiles have been conducted, yielding promising alternative treatments. Conclusions: By targeting the particular mutations found in MSI-high patients, it could help explain the chemoresistance mechanism, so promising personalized treatment approaches for esophagogastric adenocarcinomas can be clinically implemented. Sources of Funding: This project is funded by the Inez and Willena Beaton Award in Oncology, valued at $7,500 and provided by the RI-MUHC. The operating grants that support the research are $120,000 over 2 years from the Cancer Research Society, and $1,200,000 USD over 3 years given by the Department of Defense. Citation Format: Adam Hoffman, Sanjima Pal, Veena Sangwan, Lorenzo Ferri. Personalized chemotherapy treatments for microsatellite instable tumors [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 2625.

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Chakrabarti, Jayati, Vivien Koh, Shing Leng Chan, Jiang Wang, Syed Ahmed, Yoshiaki Ito, Jimmy Bok Yan So, Wei Peng Yong, and Yana Zavros. "An Organoid Approach to Target Her2/PD‐L1 Positive Gastric Cancers." FASEB Journal 34, S1 (April 2020): 1. http://dx.doi.org/10.1096/fasebj.2020.34.s1.02811.

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Uotani, Takahiro, Kosuke Murakami, Tomohisa Uchida, Shingo Tanaka, Hiroyuki Nagashima, Xi-Lei Zeng, Junko Akada, Mary Estes, David Y. Graham, and Yoshio Yamaoka. "271 - two Dimensional Human Gastric Organoid Model of Helicobacter Pylori Infection." Gastroenterology 154, no. 6 (May 2018): S—66. http://dx.doi.org/10.1016/s0016-5085(18)30678-4.

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Bertaux-Skeirik, Nina, Loryn L. Holokai, Jomaris Centeno, Li Yang, Jayati Chakrabarti, Kyle McCracken, Taylor Broda, et al. "Patient-Derived in vitro and in vivo Organoid Models of Gastric Cancer." Gastroenterology 152, no. 5 (April 2017): S106. http://dx.doi.org/10.1016/s0016-5085(17)30696-0.

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Shibata, Wataru, and Shin Maeda. "Su1723 Helicobacter Infection Promotes Mouse Gastric Organoid Growth, and Altered the Property of Gastric Stem/Progenitor Cells." Gastroenterology 144, no. 5 (May 2013): S—460. http://dx.doi.org/10.1016/s0016-5085(13)61701-1.

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Salahudeen, Ameen Abdulla, Xingnan Li, Michael Cantrell, and Calvin Jay Kuo. "Gastrointestinal organoid cultures for functional evaluation of oncogenic loci." Journal of Clinical Oncology 33, no. 3_suppl (January 20, 2015): 85. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.85.

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85 Background: Novel in vitro methods surpassing limitations of current gastrointestinal cancer models such as gastric and esophagus cancer are required to functionally validate putative oncogenic loci discovered by genome sequencing efforts. The in vitro culture of primary, non-transformed tissues as three-dimensional organoids that accurately recapitulate organ structure and physiology has diverse applications including cancer biology. Methods: Mouse wild type, or p53flox/flox in tandem with lox-stop-lox KRASG12D upper digestive tract tissue containing epithelial and mesenchymal components were cultured in an air-liquid-interface and subjected to adenovirus expressing either immunoglobulin Fc (control) or GFP tagged Cre recombinase. Results: 3-dimensional organoids were generated with histological adherence to normal tissue architecture including that seen in esophagus and were able to be maintained in long term culture. Organoids exposed to GFP tagged Cre adenovirus demonstrated green fluorescence not seen in organoids exposed to control virus. Conditional allele organoids that were exposed to Cre adenovirus demonstrated increased rate of growth compared to controls. Histology of these rapidly growing organoids demonstrated cellular features consistent with dysplasia. Conclusions: 3-dimensional organoids can be generated from upper digestive tract tissues, can undergo adenoviral mediated transfection to achieve oncogenic gene expression or inactivation resulting in dysplastic morphology. 3-dimensional organoids are therefore an attractive model to study or identify candidate oncogenic loci identified by recent genomic sequencing studies.

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Hamilton, M., Z. Mars, M. Sedeuil, M. Rolland, D. Jean, and V. Giroux. "A10 OVEREXPRESSION OF ASCL2 ALTERS DIFFERENTIATION, CELL CYCLE AND RESISTANCE TO ANTI-CANCER TREATMENT IN ESOPHAGEAL ORGANOIDS." Journal of the Canadian Association of Gastroenterology 6, Supplement_1 (March 1, 2023): 5–6. http://dx.doi.org/10.1093/jcag/gwac036.010.

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Abstract Background The esophagus is in constant contact with the austere environment caused by food and gastric reflux. It is protected by a squamous epithelium which maintenance is provided by a rare subpopulation of basal cells: Keratin 15+ (Krt15+) stem cells. However, little is known about the mechanisms underlying the expansion and the function of these stem cells. It was shown that the transcription factor ASCL2 is strongly upregulated in Krt15+ cells compared to Krt15- cells. Interestingly, ASCL2 is a gene target of the Wnt/β-catenin pathway, which acts as a regulator of proliferation and maintenance of the stemness state. Purpose The ultimate goal of my research project is to determine the role of ASCL2 in the maintenance of esophageal stem cells. To do so, I will investigate the role of ASCL2 in esophageal epithelial biology. Method Lentiviral infection approach was used to obtain mouse esophageal organoids overexpressing ASCL2 (ASCL2OE). Organoid culture, immunostaining (such as IF and H&E), qPCR, WB, mass spectrometry and proliferation assay were used to characterize the effect of ASCL2OE on morphology, differentiation, proliferation, self-renewal, and gene expression. Result(s) ASCL2OE severely altered the morphology of organoids, which were smaller and less differentiated. Defects in differentiation was investigated by IF which showed that some cells expressed both p63 and K13, respectively basal and suprabasal markers. Thus, cells seem to be blocked in an intermediate state of differentiation suggesting a default in cell fate decision. Mass spectrometry analysis confirmed a change in biological processes related to differentiation of keratinocytes and of epithelial cells. We also investigated the role of ASCL2 in self-renewal and observed that organoid formation rate (OFR) was reduced in ASCL2OE organoids. Furthermore, proliferation was also reduced in WST-1 and EdU assays. We then observed significant changes in the cell cycle by flow cytometry: there is an increased in the number of cells in G0/G1 and a major decrease in G2/M cells, suggesting a blockade in G1. Interestingly, CDNK2a (p16INK4a), an inhibitor of cell cycle progression, was increased in our mass spectrometry results. Finally, ASCL2 could also play a role in radio and chemoresistance of Krt15+ stem cells, as ASCL2OE organoids are less sensitive to radiation and chemotherapy agents than control. Conclusion(s) ASCL2 could play a role in orchestrating cell fate decision in the esophageal epithelium as ASCL2OE organoids showed alteration in differentiation, proliferation, and cell cycle. Please acknowledge all funding agencies by checking the applicable boxes below Other Please indicate your source of funding; NSERC, Canada Research Chairs and CRCHUS scolarship Disclosure of Interest None Declared

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Noto, Christine N., Kevin A. Bockerstett, Nicholas M. Jackson, Eric L. Ford, and Richard J. DiPaolo. "IL-13 promotes precancerous epithelial cell changes during autoimmune gastritis." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 221.5. http://dx.doi.org/10.4049/jimmunol.204.supp.221.5.

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Abstract Individuals with chronic autoimmune diseases have an increased risk of cancer development in the affected organ. Cytokines released during chronic inflammation regulate tissue repair processes and can contribute to an increased risk of carcinogenesis. However, the identities and mechanisms by which cytokines regulate cancer development is poorly understood. In these studies, a TCR transgenic mouse model of autoimmune gastritis (AIG) was used to determine the cellular sources of IL-13 and the molecular mechanisms by which IL-13 promotes precancerous epithelial cell changes in a setting of chronic inflammation. Using this model, we identified IL-13 secreting CD4+ T cells, ILC2s, and mast cells present in the mucosa of chronically inflamed stomachs. The use of both murine and human 3D gastric organoid cultures established that IL-13 acted directly on the gastric epithelium and regulated epithelial cell survival, growth, and differentiation. Neutralizing IL-13 in mice with AIG prevented many of the precancerous cellular changes associated with gastric carcinogenesis. Finally, single-cell RNA sequencing of gastric epithelial cells with and without IL-13 receptors identified the transcriptional responses of mucosal epithelium to IL-13 during chronic autoimmunity. These studies have identified that tissue-specific IL-13 production during autoimmunity acts directly on the gastric epithelium to induce cellular changes associated with gastric cancer.

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Morrow, Riley J., Matthias Ernst, and Ashleigh R. Poh. "Longitudinal quantification of mouse gastric tumor organoid viability and growth using luminescence and microscopy." STAR Protocols 4, no. 1 (March 2023): 102110. http://dx.doi.org/10.1016/j.xpro.2023.102110.

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Jangphattananont, Nawaphat, Hiroki Sato, Ryu Imamura, Katsuya Sakai, Yumi Terakado, Kazuhiro Murakami, Nick Barker, et al. "Distinct Localization of Mature HGF from its Precursor Form in Developing and Repairing the Stomach." International Journal of Molecular Sciences 20, no. 12 (June 17, 2019): 2955. http://dx.doi.org/10.3390/ijms20122955.

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Hepatocyte growth factor (HGF) is secreted as an inactive single-chain HGF (scHGF); however, only proteolytically processed two-chain HGF (tcHGF) can activate the MET receptor. We investigated the localization of tcHGF and activated/phosphorylated MET (pMET) using a tcHGF-specific antibody. In day 16.5 mouse embryos, total HGF (scHGF + tcHGF) was mainly localized in smooth muscle cells close to, but separate from, MET-positive epithelial cells in endodermal organs, including the stomach. In the adult stomach, total HGF was localized in smooth muscle cells, and tcHGF was mainly localized in the glandular base region. Immunostaining for pMET and Lgr5-driven green fluorescent protein (GFP) indicated that pMET localization overlapped with Lgr5+ gastric stem cells. HGF promoted organoid formation similar to EGF, indicating the potential for HGF to promote the survival and growth of gastric stem cells. pMET and tcHGF localizations changed during regeneration following gastric injury. These results indicate that MET is constantly activated in gastric stem cells and that the localization of pMET differs from the primary localization of precursor HGF but has a close relationship to tcHGF. Our results suggest the importance of the microenvironmental generation of tcHGF in the regulation of development, regeneration, and stem cell behavior.

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Brew, Tom, Nicola Bougen-Zhukov, Wilson Mitchell, Lyvianne Decourtye, Emily Schulpen, Yasmin Nouri, Tanis Godwin, and Parry Guilford. "Loss of E-Cadherin Leads to Druggable Vulnerabilities in Sphingolipid Metabolism and Vesicle Trafficking." Cancers 14, no. 1 (December 26, 2021): 102. http://dx.doi.org/10.3390/cancers14010102.

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Germline inactivating variants of CDH1 are causative of hereditary diffuse gastric cancer (HDGC), a cancer syndrome characterized by an increased risk of both diffuse gastric cancer and lobular breast cancer. Because loss of function mutations are difficult to target therapeutically, we have taken a synthetic lethal approach to identify targetable vulnerabilities in CDH1-null cells. We have previously observed that CDH1-null MCF10A cells exhibit a reduced rate of endocytosis relative to wildtype MCF10A cells. To determine whether this deficiency is associated with wider vulnerabilities in vesicle trafficking, we screened isogenic MCF10A cell lines with known inhibitors of autophagy, endocytosis, and sphingolipid metabolism. Relative to wildtype MCF10A cells, CDH1−/− MCF10A cells showed significantly greater sensitivity to several drugs targeting these processes, including the autophagy inhibitor chloroquine, the endocytosis inhibitors chlorpromazine and PP1, and the sphingosine kinase 1 inhibitor PF-543. Synthetic lethality was confirmed in both gastric and mammary organoid models of CDH1 loss, derived from CD44-Cre/Cdh1fl/fl/tdTomato mice. Collectively, these results suggest that both sphingolipid metabolism and vesicle trafficking represent previously unrecognised druggable vulnerabilities in CDH1-null cells and may lead to the development of new therapies for HDGC.

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Yan, Helen H. N., Hoi Cheong Siu, Simon Law, Siu Lun Ho, Sarah S. K. Yue, Wai Yin Tsui, Dessy Chan, et al. "A Comprehensive Human Gastric Cancer Organoid Biobank Captures Tumor Subtype Heterogeneity and Enables Therapeutic Screening." Cell Stem Cell 23, no. 6 (December 2018): 882–97. http://dx.doi.org/10.1016/j.stem.2018.09.016.

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Li, Jie, Huawei Xu, Lixing Zhang, Lele Song, Dan Feng, Xiaobo Peng, Meihong Wu, et al. "Malignant ascites-derived organoid (MADO) cultures for gastric cancer in vitro modelling and drug screening." Journal of Cancer Research and Clinical Oncology 145, no. 11 (October 9, 2019): 2637–47. http://dx.doi.org/10.1007/s00432-019-03004-z.

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Lowenthal, Brett M., Theresa W. Chan, John A. Thorson, Kaitlyn J. Kelly, Thomas J. Savides, and Mark A. Valasek. "Gastric Medullary Carcinoma with Sporadic Mismatch Repair Deficiency and a TP53 R273C Mutation: An Unusual Case with Wild-Type BRAF." Case Reports in Pathology 2017 (2017): 1–5. http://dx.doi.org/10.1155/2017/3427343.

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Medullary carcinoma has long been recognized as a subtype of colorectal cancer associated with microsatellite instability and Lynch syndrome. Gastric medullary carcinoma is a very rare neoplasm. We report a 67-year-old male who presented with a solitary gastric mass. Total gastrectomy revealed a well-demarcated, poorly differentiated carcinoma with an organoid growth pattern, pushing borders, and abundant peritumoral lymphocytic response. The prior cytology was cellular with immunohistochemical panel consistent with upper gastrointestinal/pancreaticobiliary origin. Overall, the histopathologic findings were consistent with gastric medullary carcinoma. A mismatch repair panel revealed a mismatch repair protein deficient tumor with loss of MLH1 and PMS2 expression. BRAF V600E immunostain (VE1) and BRAF molecular testing were negative, indicating a wild-type gene. Tumor sequencing of MLH1 demonstrated a wild-type gene, while our molecular panel identified TP53 c.817C>T (p.R273C) mutation. These findings were compatible with a sporadic tumor. Given that morphologically identical medullary tumors often occur in Lynch syndrome, it is possible that mismatch repair loss is an early event in sporadic tumors with p53 mutation being a late event. Despite having wild-type BRAF, this tumor is sporadic and unrelated to Lynch syndrome. This case report demonstrates that coordinate ancillary studies are needed to resolve sporadic versus hereditary rare tumors.

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Li, Huan, Xinghan Jin, Shiwei Zhang, Bo Li, Leli Zeng, Yulong He, and Changhua Zhang. "APY0201 Represses Tumor Growth through Inhibiting Autophagy in Gastric Cancer Cells." Journal of Oncology 2022 (June 24, 2022): 1–16. http://dx.doi.org/10.1155/2022/7104592.

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Gastric cancer (GC) is one of the most common cancers globally. There are currently few effective chemotherapeutic drugs available for GC patients. The inhibitors of phosphatidylinositol kinase containing an FYVE finger structure (PIKfyve) have shown significant anticancer effects in several types of cancers, but their effectiveness in GC remains unknown. In this study, we investigate the effect of APY0201, an inhibitor of PIKfyve, on GC tumor growth and its mechanism of action. It was found that APY0201 inhibited GC cell proliferation in in vitro GC cell model, organoid model, and in vivo xenograft tumor model. Through analyzing cell autophagy, we found that APY0201 might block autophagic flux by impairing lysosome degradation function of GC cells, inducing the accumulation of autophagosomes, thus causing the inhibition of GC cell proliferation. We also found that APY0201 induced G1/S phase arrest in GC cells. Importantly, APY0201 was also effective in inducing repression of autophagy and cell cycle arrest in the mouse tumor xenograft. Our results suggest that APY0201 could be a new promising therapeutic option for GC.

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Nowicki-Osuch, Karol, Lizhe Zhuang, Sriganesh Jammula, Christopher W. Bleaney, Krishnaa T. Mahbubani, Ginny Devonshire, Annalise Katz-Summercorn, et al. "Molecular phenotyping reveals the identity of Barrett’s esophagus and its malignant transition." Science 373, no. 6556 (August 12, 2021): 760–67. http://dx.doi.org/10.1126/science.abd1449.

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The origin of human metaplastic states and their propensity for cancer is poorly understood. Barrett’s esophagus is a common metaplastic condition that increases the risk for esophageal adenocarcinoma, and its cellular origin is enigmatic. To address this, we harvested tissues spanning the gastroesophageal junction from healthy and diseased donors, including isolation of esophageal submucosal glands. A combination of single-cell transcriptomic profiling, in silico lineage tracing from methylation, open chromatin and somatic mutation analyses, and functional studies in organoid models showed that Barrett’s esophagus originates from gastric cardia through c-MYC and HNF4A-driven transcriptional programs. Furthermore, our data indicate that esophageal adenocarcinoma likely arises from undifferentiated Barrett’s esophagus cell types even in the absence of a pathologically identifiable metaplastic precursor, illuminating early detection strategies.

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Yu, Byeong Min, Yong Chan Lee, CHANG Y. JUNG, So Dam Lee, Bo Ram Hwang, and Ki Taek Nam. "Tu1196 EFFECT OF HELICOBACTER PYLORI ON THE JUNCTIONAL PROTEIN EXPRESSIONS IN THE NORMAL HUMAN GASTRIC EPITHELIAL CELL DERIVED FROM GASTRIC ORGANOID IN VITRO." Gastroenterology 158, no. 6 (May 2020): S—1014—S—1015. http://dx.doi.org/10.1016/s0016-5085(20)33207-8.

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Chakrabarti, Jayati, Vivien Koh, Shing-Leng Chan, Jiang Wang, Syed Ahmad, Yoshiaki Ito, Jimmy Bok Yan So, Wei Peng Yong, and Yana Zavros. "590 AN ORGANOID-IMMUNE CELL CO-CULTURE PREDICTIVE MODEL TO TARGET HER2/PD-L1 POSITIVE GASTRIC CANCERS." Gastroenterology 158, no. 6 (May 2020): S—126. http://dx.doi.org/10.1016/s0016-5085(20)30996-3.

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Matsuzawa, Kenji, Taiji Akamatsu, and Tsutomu Katsuyama. "Mucin histochemistry of pancreatic duct cell carcinoma, with special reference to organoid differentiation simulating gastric pyloric mucosa." Human Pathology 23, no. 8 (August 1992): 925–33. http://dx.doi.org/10.1016/0046-8177(92)90407-t.

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Dotti, Isabella, Rut Mora-Buch, Elena Ferrer-Picón, Núria Planell, Peter Jung, M. Carme Masamunt, Raquel Franco Leal, et al. "Alterations in the epithelial stem cell compartment could contribute to permanent changes in the mucosa of patients with ulcerative colitis." Gut 66, no. 12 (November 1, 2016): 2069–79. http://dx.doi.org/10.1136/gutjnl-2016-312609.

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ObjectiveUC is a chronic inflammatory disease of the colonic mucosa. Growing evidence supports a role for epithelial cell defects in driving pathology. Moreover, long-lasting changes in the epithelial barrier have been reported in quiescent UC. Our aim was to investigate whether epithelial cell defects could originate from changes in the epithelial compartment imprinted by the disease.DesignEpithelial organoid cultures (EpOCs) were expanded ex vivo from the intestinal crypts of non-IBD controls and patients with UC. EpOCs were induced to differentiate (d-EpOCs), and the total RNA was extracted for microarray and quantitative real-time PCR (qPCR) analyses. Whole intestinal samples were used to determine mRNA expression by qPCR, or protein localisation by immunostaining.ResultsEpOCs from patients with UC maintained self-renewal potential and the capability to give rise to differentiated epithelial cell lineages comparable with control EpOCs. Nonetheless, a group of genes was differentially regulated in the EpOCs and d-EpOCs of patients with UC, including genes associated with antimicrobial defence (ie,LYZ,PLA2G2A), with secretory (ie,ZG16,CLCA1) and absorptive (ie,AQP8,MUC12) functions, and with a gastric phenotype (ie,ANXA10,CLDN18andLYZ). A high rate of concordance was found in the expression profiles of the organoid cultures and whole colonic tissues from patients with UC.ConclusionsPermanent changes in the colonic epithelium of patients with UC could be promoted by alterations imprinted in the stem cell compartment. These changes may contribute to perpetuation of the disease.

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Thanh Huong, Phung, Sanjeev Gurshaney, Nguyen Thanh Binh, Anh Gia Pham, Huy Hoang Nguyen, Xuan Thanh Nguyen, Hai Pham-The, et al. "Emerging Role of Circulating Tumor Cells in Gastric Cancer." Cancers 12, no. 3 (March 15, 2020): 695. http://dx.doi.org/10.3390/cancers12030695.

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With over 1 million incidence cases and more than 780,000 deaths in 2018, gastric cancer (GC) was ranked as the 5th most common cancer and the 3rd leading cause of cancer deaths worldwide. Though several biomarkers, including carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9), and cancer antigen 72-4 (CA72-4), have been identified, their diagnostic accuracies were modest. Circulating tumor cells (CTCs), cells derived from tumors and present in body fluids, have recently emerged as promising biomarkers, diagnostically and prognostically, of cancers, including GC. In this review, we present the landscape of CTCs from migration, to the presence in circulation, biologic properties, and morphologic heterogeneities. We evaluated clinical implications of CTCs in GC patients, including diagnosis, prognosis, and therapeutic management, as well as their application in immunotherapy. On the one hand, major challenges in using CTCs in GC were analyzed, from the differences of cut-off values of CTC positivity, to techniques used for sampling, storage conditions, and CTC molecular markers, as well as the unavailability of relevant enrichment and detection techniques. On the other hand, we discussed future perspectives of using CTCs in GC management and research, including the use of circulating tumor microembolies; of CTC checkpoint blockade in immunotherapy; and of organoid models. Despite the fact that there are remaining challenges in techniques, CTCs have potential as novel biomarkers and/or a non-invasive method for diagnostics, prognostics, and treatment monitoring of GC, particularly in the era of precision medicine.

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Lo, Yuan-Hung, Kevin S. Kolahi, Yuhong Du, Chiung-Ying Chang, Andrey Krokhotin, Ajay Nair, Walter D. Sobba, et al. "A CRISPR/Cas9-Engineered ARID1A-Deficient Human Gastric Cancer Organoid Model Reveals Essential and Nonessential Modes of Oncogenic Transformation." Cancer Discovery 11, no. 6 (January 15, 2021): 1562–81. http://dx.doi.org/10.1158/2159-8290.cd-20-1109.

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Lo, Yuan-Hung, Kevin Kolahi, Yuhong Du, Chiung-Ying Chang, Andrey Krokhotin, Ajay Nair, Walter Sobba, et al. "Sa134 A CRISPR/CAS9-ENGINEERED ARID1A-DEFICIENT HUMAN GASTRIC CANCER ORGANOID MODEL REVEALS ESSENTIAL AND NON-ESSENTIAL MODES OF ONCOGENIC TRANSFORMATION." Gastroenterology 160, no. 6 (May 2021): S—432. http://dx.doi.org/10.1016/s0016-5085(21)01747-9.

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Journal articles on the topic 'Gastric organoid'

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