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A Tumour-Resident Lgr5+ Stem Cell - Like Pool Drives the Establishment and Progression of Advanced Gastric Cancers

ABSTRACT: Gastric cancer is amongst the most prevalent and deadliest cancers globally. To derive mechanistic insight into the pathways governing this disease, we generated a stomach-specific Claudin18-IRES-CreERT2 mouse line to model advanced human gastric cancer and investigated the role of tumour resident Lgr5+ stem-like cells in gastric cancer. Mouse lines incorporating Cldn18-driven conditional dysregulation of the Wnt, RTK and Trp53 pathways modelled metastatic Chromosomal Instable-type gastric cancer. In parallel, we supplemented these cancer models with orthotopic transplantation of cancer organoids to derive detailed mechanistic insight into the roles of Lgr5+ cancer stem cell in gastric cancer. Here we show, we recapitulated advanced human gastric cancer in terms of disease phenotype, aberrant gene expression profile, molecular markers, and sites of distant metastases. Importantly, we established that tumour-resident Lgr5+ stem-like cells are critical to the initiation and maintenance of tumour burden, and are obligatory for the establishment of metastases. These models will be invaluable for deriving clinically-relevant mechanistic insights into cancer progression and as pre-clinical models for evaluating novel therapeutics.

ORGANISM(S): Mus musculus

PROVIDER: GSE184613 | GEO | 2021/11/26

REPOSITORIES: GEO

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Project description:Carcinoma-associated fibroblasts (CAFs) that express ?-smooth-muscle-actin (?SMA+) contribute to cancer progression, but their precise origin and role in tumorigenesis is not established. Using mouse models of inflammation-induced gastric cancer, we show that at least 20% of CAFs originate from bone marrow and derive from mesenchymal stem cells (MSCs). Surprisingly, we find that ?SMA+ myofibroblasts (MF) are niche cells normally present in bone marrow and increase markedly in the bone marrow and blood during progression to dysplasia. MSC-derived CAFs that are recruited to the dysplastic stomach express IL-6, Wnt5? and BMP4 and show DNA hypomethylation. Bone marrow (BM)-derived CAFs strongly promote tumor growth in organotypic and xenograft models. In addition, CAFs are generated from MSCs and are recruited to distant tumor sites in a TGF-?- and SDF-1?-dependent manner. Carcinogenesis therefore involves the expansion and relocation of normal bone marrow niche cells to the tumor site where they create a new niche to sustain cancer progression. Since resident (non-BM-derived) CAFs could not be cultured and directly compared to BM-derived CAFs, we additionally isolated total RFP(+) gastric CAFs from aSMA-RFP mice with Helicobacter felis-induced dysplasia, and compared them to GFP(+) BM-derived gastric CAFs from mice with H. felis-induced dysplasia mice that had been transplanted with UBC-EGFP bone marrow. The RFP+ CAFs (HF CAF) represent total CAFs (of which only 20% were BM-derived), while the latter represented only BM-derived CAFs (BM CAF). We compared their gene expression using the Illumina array (MouseWG-6v2) directly after FACS sorting. Interestingly, the GFP+ BM-derived CAFs expressed higher levels of inflammatory genes (IL-6, IL-1?, IL-33) and a number of tumor and stem cell associated factors (CCL5, SPP1, Notch3, MMP9, CD47, CXCR4, PARP10,) compared to the total (RFP+) population of gastric CAFs. Comparison of bone marrow-derived GFP-labeled gastric CAFs versus all gastric CAFs.

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A Tumour-Resident Lgr5+ Stem Cell - Like Pool Drives the Establishment and Progression of Advanced Gastric Cancers

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