Mouse Models of Human Gastric Cancer Subtypes With Stomach-Specific CreERT2-Mediated Pathway Alterations

Seidlitz, Therese; Chen, Yi-Ting; Uhlemann, Heike; Schölch, Sebastian; Kochall, Susan; Merker, Sebastian R.; Klimová, Anna; Hennig, Alexander; Schweitzer, Christine; Pape, Kristin; Baretton, Gustavo; Welsch, Thilo; Aust, Daniela E.; Weitz, Jürgen; Koo, Bon–Kyoung; Stange, Daniel E.

doi:10.1053/j.gastro.2019.09.026

Cited by 57 publications

(56 citation statements)

References 45 publications

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“…Although our transgenic GC mouse models (LSL-hMYH9; Atp4b-cre; Tff1 -/- mice and Myh9 fl/fl ; Atp4b-cre; Tff1 -/- mice) supported the finding that MYH9-mediated CTNNB1 transcription promotes tumor progression (proliferation and invasion) and shortens the survival of Tff1 -/- mice, we failed to find peritoneal metastasis in our models. Therefore, other GC mouse models prone to peritoneal metastasis should to be introduced for further study 45 . Although STS was confirmed to significantly inhibit nuclear MYH9 phosphorylation at S1943 and GC metastasis, it is a pan-kinase inhibitor, and how to improve the intracellular nuclear targeting of STS requires further research.…”

Section: Discussionmentioning

confidence: 99%

Nuclear MYH9-induced CTNNB1 transcription, targeted by staurosporin, promotes gastric cancer cell anoikis resistance and metastasis

et al. 2020

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Rationale: Peritoneal metastasis predicts poor prognosis of gastric cancer (GC) patients, and the underlying mechanisms are poorly understood. Methods: The 2-DIGE, MALDI-TOF/TOF MS and single-cell transcriptome were used to detect differentially expressed proteins among normal gastric mucosa, primary GC and peritoneal metastatic tissues. Lentiviruses carrying shRNA and transcription activator-like effector nuclease technology were used to knock down myosin heavy chain 9 (MYH9) expression in GC cell lines. Immunofluorescence, immune transmission electron microscopy, chromatin fractionation, co-immunoprecipitation, and assays for chromatin immunoprecipitation, dual luciferase reporter, agarose-oligonucleotide pull-down, flow cytometry and cell anoikis were performed to uncover nuclear MYH9-induced β-catenin ( CTNNB1 ) transcription in vitro . Nude mice and conditional transgenic mice were used to investigate the findings in vivo . Results: We observed that MYH9 was upregulated in metastatic GC tissues and was associated with a poor prognosis of GC patients. Mechanistically, we confirmed that MYH9 was mainly localized in the GC cell nuclei by four potential nuclear localization signals. Nuclear MYH9 bound to the CTNNB1 promoter through its DNA-binding domain, and interacted with myosin light chain 9, β-actin and RNA polymerase II to promote CTNNB1 transcription, which conferred resistance to anoikis in GC cells in vitro and in vivo . Staurosporine reduced nuclear MYH9 S1943 phosphorylation to inhibit CTNNB1 transcription, Wnt/β-catenin signaling activation and GC progression in both orthotropic xenograft GC nude mouse and transgenic GC mouse models. Conclusion: This study identified that nuclear MYH9-induced CTNNB1 expression promotes GC metastasis, which could be inhibited by staurosporine, indicating a novel therapy for GC peritoneal metastasis.

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Section: Discussionmentioning

confidence: 99%

Nuclear MYH9-induced CTNNB1 transcription, targeted by staurosporin, promotes gastric cancer cell anoikis resistance and metastasis

et al. 2020

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“…Moreover, a potential GSDMB-mediated immune rejection of gastric tumor cells, as described by Zhou et al [35] is unlikely in our model since GSDMB2 is expressed also in immunocytes. Therefore, evaluating further the functional role of GSDMB isoforms in gastric cancer will require future studies using the recently described stomach-specific gene promoters [55] and/or crossing GSDMB models with GEMMs that develop gastric carcinomas [56].…”

Section: Discussionmentioning

confidence: 99%

In Vivo Analysis of the Role of Gasdermin-B (Gsdmb) in Cancer Using Novel Knock-in Mouse Models

Sarrió

Rojo-Sebastián

Teijo

et al. 2021

Preprint

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Background: Gasdermin-B gene (GSDMB) is frequently over-expressed in tumors, and its shortest translated variant (isoform 2; GSDMB2) increases aggressive behavior in breast cancer cells. Paradoxically, GSDMB could have either pro-tumor or tumor suppressor properties depending on the biological context. Since GSDMB gene is not present in the mouse genome, deciphering fully the functional roles of GSDMB in cancer requires novel in vivo models. Methods: We first generated by gene targeting a conditional knock-in mouse model (R26-STOP-GB2) harboring human GSDMB2 transcript within the ROSA26 locus. We next derived the R26-GB2 model ubiquitously expressing GSDMB2 in multiple tissues (confirmed by western blot and immunohistochemistry) and performed a comprehensive histopathological analysis in multiple tissues from 75 male and female mice up to 18 months of age. Additionally, we produced the double transgenic model R26-GB2/MMTV-PyMT, co-expressing GSDMB2 and the Polyoma-Middle-T oncogene, and assessed breast cancer generation and progression in GSDMB2-homozygous (n=10) and control (n=17) female mice up to 15 weeks of age. Results: In the R26-GB2 model, which showed different GSDMB2 cytoplasmic and/or nuclear localization among tissues, we investigated if GSDMB2 expression had intrinsic tumorigenic activity. 41% of mice developed spontaneous lung tumors, but neither the frequency nor the histology of these neoplasias was significantly different from wildtype animals. Strikingly, while 17% control mice developed gastric carcinomas, no GSDMB2-positive mice did. No other tumor types or additional histological alterations were frequently seen in these mice. In the R26-GB2/MMTV-PyMT model, the strong nucleus-cytoplasmic GSDMB2 expression in breast cancer cells did not significantly affect cancer formation (number of tumors, latency, tumor weight, histology or proliferation) or lung metastasis potential compared to controls. Conclusions: GSDMB2 expression alone does not have an overall tumorigenic potential in mice, but it might reduce gastric carcinogenesis. Contrary to human cancers, GSDMB2 upregulation does not significantly affect breast cancer generation and progression in mouse models. However, to evidence the GSDMB functions in cancer and other pathologies in vivo may require the presence of specific stimulus or cellular contexts. Our novel mouse strains will serve as the basis for the future development of more precise tissue-specific and context-dependent cancer models.

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“…In a recent study, Seidlitz et al used lineage tracing technology to establish a CreERT2 mouse model with a phenotype similar to that of human gastric cancer. Then, they extracted tumor tissue from these mice and investigated the effects of chemotherapeutic drugs and various pathway inhibitors [117]. In summary, lineage tracing can be used not only to explore the presence and differentiation potential of gastric stem cells but also to study their role in disease models to support the discovery of tumor stem cell-targeted drugs for clinical application.…”

Section: The Stomachmentioning

confidence: 99%

Lineage tracing: technology tool for exploring the development, regeneration, and disease of the digestive system

et al. 2020

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Lineage tracing is the most widely used technique to track the migration, proliferation, and differentiation of specific cells in vivo. The currently available gene-targeting technologies have been developing for decades to study organogenesis, tissue injury repairing, and tumor progression by tracing the fates of individual cells. Recently, lineage tracing has expanded the platforms available for disease model establishment, drug screening, cell plasticity research, and personalized medicine development in a molecular and cellular biology perspective. Lineage tracing provides new views for exploring digestive organ development and regeneration and techniques for digestive disease causes and progression. This review focuses on the lineage tracing technology and its application in digestive diseases.

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Mouse Models of Human Gastric Cancer Subtypes With Stomach-Specific CreERT2-Mediated Pathway Alterations

Cited by 57 publications

References 45 publications

Nuclear MYH9-induced CTNNB1 transcription, targeted by staurosporin, promotes gastric cancer cell anoikis resistance and metastasis

Nuclear MYH9-induced CTNNB1 transcription, targeted by staurosporin, promotes gastric cancer cell anoikis resistance and metastasis

In Vivo Analysis of the Role of Gasdermin-B (Gsdmb) in Cancer Using Novel Knock-in Mouse Models

Lineage tracing: technology tool for exploring the development, regeneration, and disease of the digestive system

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