Abstract
Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFβ signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFβ-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1+) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature. These features are recapitulated in human BRAF-mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFβ-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells.
Highlights
Right-sided colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFβ signalling
Rightsided CRCs are thought to arise through an alternative serrated neoplasia pathway so-called because the precursor lesions—namely, hyperplastic polyps, sessile serrated adenomas/ lesions (SSAs), and traditional serrated adenomas (TSAs)—are distinguished by a distinctive saw-tooth crypt morphology caused by marked infolding of the upper crypt epithelium[6,7,8]
In addition to the saw-tooth crypt architecture seen in longitudinal sections, right-sided tumours often exhibit other common histopathological features, including a flat/sessile morphology, and a mucinous histology, as well as a propensity towards aggressive local invasion with peritoneal metastases/carcinomatosis9–13. Rightsided CRCs (rCRCs) carry a worse prognosis than their left-sided counterparts and are characterised by microsatellite instability (MSI) and aberrations in MAPK, TGFβ, and mismatch repair pathways[9,10,11]
Summary
Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFβ signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1+) and, importantly, lack expression of Lgr[5] and its associated intestinal stem cell signature These features are recapitulated in human BRAF-mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. We describe a human-like mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFβ-receptor signalling that develops proximal colonic tumours with a foetal-like progenitor phenotype (Ly6a/Sca1+) and, importantly, lack expression of Lgr[5] and its associated intestinal stem cell signature. Whether induced directly by oncogenic BRAF or by inflammation, we show that the tumorigenic potential of these foetal-like progenitor populations is fundamentally restrained by epithelial TGFβ signalling
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