A tumour-resident Lgr5+ stem-cell-like pool drives the establishment and progression of advanced gastric cancers

Fatehullah, Aliya; Terakado, Yumi; Sagiraju, Sowmya; Tan, T. L.; Sheng, Taotao; Tan, Shawna; Murakami, Kazuhiro; Yada, Swathi; Ang, Nicholas; Rajarethinam, Ravisankar; Ming, Tan; Tan, Patrick; Lee, B.; Barker, Nick

doi:10.1038/s41556-021-00793-9

Cited by 49 publications

(45 citation statements)

References 64 publications

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“…Lgr5, an orphan G protein coupled receptor, has been identified as a marker of frequently cycling gastric epithelial stem cells residing at the base of the antral gland [25,32]. Our and other groups have demonstrated that mutant Lgr5 + cells can initiate gastric cancer and accelerate the progression and metastasis of gastric cancer [5,[33][34][35]. We detected the Lgr5 + cell number in Prmt5 mutant mice.…”

Section: Lgr5 + Stem Cells Were Dramatically Increased In the Invasiv...mentioning

confidence: 69%

PRMT5 acts as a tumor suppressor by inhibiting Wnt/β-catenin signaling in murine gastric tumorigenesis

et al. 2022

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Previous studies have demonstrated the in vitro oncogenic role of protein arginine methyltransferase 5 (PRMT5) in gastric cancer cell lines. The in vivo function of PRMT5 in gastric tumorigenesis, however, is still unexplored. Here, we showed that Prmt5 deletion in mouse gastric epithelium resulted in spontaneous tumorigenesis in gastric antrum. All Prmt5-deficient mice displayed intestinal-type gastric cancer within 4 months of age. Of note, 20% (2/10) of Prmt5 mutants finally developed into invasive gastric cancer by 8 months of age. Gastric cancer caused by PRMT5 loss exhibited the increase in Lgr5 + stem cells, which are proposed to contribute to both the gastric tumorigenesis and progression in mouse models. Consistent with the notion that Lgr5 is the target of Wnt/β-catenin signaling, whose activation is the most predominant driver for gastric tumorigenesis, Prmt5 mutant gastric cancer showed the activation of Wnt/β-Catenin signaling. Furthermore, in human gastric cancer samples, PRMT5 deletion and downregulation were frequently observed and associated with the poor prognosis. We propose that as opposed to the tumor-promoting role of PRMT5 well-established in the progression of various cancer types, PRMT5 functions as a tumor suppressor in vivo, at least during gastric tumor formation.

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Section: Lgr5 + Stem Cells Were Dramatically Increased In the Invasiv...mentioning

confidence: 69%

PRMT5 acts as a tumor suppressor by inhibiting Wnt/β-catenin signaling in murine gastric tumorigenesis

et al. 2022

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“…Moreover, synchronous cohorts of animals that will develop genotypically defined tumors can be produced in a day, thereby greatly simplifying the execution of mechanistic and preclinical studies. As such, gastric cancer EPO-GEMMs offer advantages over carcinogen-induced models, which do not produce genetically defined tumors [50][51][52] , and Cre/lox-based models, which are limited to available germline strains, yield asynchronous cohorts, and produce substantial animal waste as unavoidable byproducts of strain intercrossing 22,23 . Furthermore, EPO-GEMMs produce focal cancers in adult mice, avoiding the confounding effects of tissue-wide gene activation/inactivation during embryogenesis or, conversely, the requirement for tamoxifen (which can induce gastric metaplasia [53][54][55] ) to recombine germline alleles later on.…”

Section: Discussionmentioning

confidence: 99%

“…Owing to their ability to capture tumor development in the complexity of the whole organism, genetically engineered mouse models (GEMMs) have proven to be a valuable tool for understanding genotype-phenotype relationships and evaluating new therapeutic concepts in a range of tumor types. However, due to the cost and waste of intercrossing various germline strains, traditional GEMMs are time and resource-consuming, making it difficult to model and interrogate the spectrum of tumor genotypes that exists in patients or conduct large-scale preclinical studies [20][21][22][23] . Likewise, it is extremely cumbersome to interrogate the genetics of tumorhost interactions, as the number of intercrosses needed to produce a genetically defined cancer and in an altered host strain is prohibitive.…”

Section: Introductionmentioning

confidence: 99%

Somatic mouse models of gastric cancer reveal genotype-specific features of metastatic disease

Leibold

Amor

Tsanov

et al. 2022

Preprint

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Metastatic gastric carcinoma is a highly lethal cancer that responds poorly to conventional and molecularly targeted therapies. Despite its clinical relevance, the mechanisms underlying the behavior and therapeutic response of this disease are poorly understood owing, in part, to a paucity of tractable models that faithfully recapitulate different subtypes of the human disease. To close this gap, we developed methods to somatically introduce different oncogenic lesions directly into the stomach epithelium and show that genotypic configurations observed in patients produce metastatic gastric cancers that recapitulate the histological, molecular, and clinical features of all non-viral molecular subtypes of the human disease. Applying this platform to both wild-type and immune-deficient mice revealed previously unappreciated links between the genotype, organotropism and immune surveillance of metastatic cells that produced distinct patterns of metastasis that were mirrored in patients. Our results establish and credential a highly portable platform for producing autochthonous cancer models with flexible genotypes and host backgrounds, which can unravel mechanisms of gastric tumorigenesis or test new therapeutic concepts aimed at improving outcomes in gastric cancer patients.

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“…The present study found that embryonic development-related genes were prognostic risk factors for BLCA. Invasion and metastasis of BLCA are thought to be associated with EMT [30,31].Tumor cell stemness regulates tumor cell differentiation, proliferation, invasion and migration [4,[32][33][34].Numerous studies showed that cancer stem cells regulate EMT [35][36][37].Embryonic development is often closely related to stem cells and EMT [5,38,39]. Therefore, we established a micro-landscape of embryonic development-related genes for predicting prognostic risk in BLCA patients.…”

Section: Discussionmentioning

confidence: 99%

GATA2 as an outcome signature: promoting bladder cancer migration and inhibiting PD-L1 expression

Sun

2022

Preprint

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BackgroundEmbryonic development is regulated by stem cells, and epithelial-to-mesenchymal transition (EMT) is associated with cell stemness ; nevertheless, the EMT regulation by embryonic development-related genes has not been studied. Immune checkpoints exert an essential effect in tumor treatment ; however, their regulatory mechanisms have not been fully elucidated. MethodsWe obtained clinicopathological and transcriptome data from The Cancer Genome Atlas. Embryonic development- associated genes were obtained from The Human Gene Database. We identified genes using univariate Cox regression analysis and identified various subtypes using consensus clustering analysis. Immunoassays were performed using the CIBERSORT package and Estimation of Stromal and Immune cells in the Malignant Tumor tissues using an expression data algorithm. The least absolute shrinkage and selection operator algorithm and multivariate Cox regression analysis were adopted to generate the prognostic model. We used the OCLR and TIDE algorithms. We conducted functional experiments.ResultsTwenty-two embryonic development-associated genes were risk factors for bladder cancer, and their expression levels significantly correlated with the TNM stage. We assessed the extent of immune infiltration, regulation of immune checkpoints, and responses to immune checkpoint blockade based on these genes. These risk genes were associated with EMT and modulated immune checkpoints. Cellular experiments demonstrated that EVC2 and GATA2 drive BLCA invasion and migration. GATA2 regulated the PD-L1 expression.ConclusionWe identified three critical genes: RUNX2, GATA2 and EVC2. These three genes are related to EMT and immune cell infiltration and are independent prognostic elements for BLCA.

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A tumour-resident Lgr5+ stem-cell-like pool drives the establishment and progression of advanced gastric cancers

Cited by 49 publications

References 64 publications

PRMT5 acts as a tumor suppressor by inhibiting Wnt/β-catenin signaling in murine gastric tumorigenesis

PRMT5 acts as a tumor suppressor by inhibiting Wnt/β-catenin signaling in murine gastric tumorigenesis

Somatic mouse models of gastric cancer reveal genotype-specific features of metastatic disease

GATA2 as an outcome signature: promoting bladder cancer migration and inhibiting PD-L1 expression

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