Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis

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.

Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps

“…Shown more recently, microbial dysbiosis can also be an environmental trigger for hypermethylation ( DeStefano Shields et al, 2021 ). Antibiotic suppression of the microbiota reduces colonic tumorigenesis in a Braf mutant model ( Leach et al, 2021 ), whereas in another study, enterotoxigenic Bacteroides fragilis (ETBF) infection is a required trigger for tumorigenesis in the proximal mid-colon in a Braf mutant mouse model ( DeStefano Shields et al, 2021 ). In the latter report, the earliest events of the ETBF response in epithelial cells prior to tumor formation occur at the colonic mucosal surface, where colonic epithelial cells and luminal contents interact.…”

“…We propose a new paradigm in which damage to the proximal colon, possibly from microbiota, initiates a metaplastic cascade that may eventually select for survival/proliferative pathways, such as activating BRAF mutations. Reversion to a fetal developmental identity is a feature of WNT-independent tumorigenesis found in recent mouse models ( Han et al, 2020 ), which can be triggered by MAPK activation either via Braf -activating mutations, epithelial damage response, or stress triggered by mismatch repair deficiency ( Bommi et al, 2021 ; Leach et al, 2021 ). Critically, Braf mutations in mouse models must be accompanied by a “second hit,” such as perturbation of transforming growth factor-β (TGF-β) signaling, for tumor induction ( Han et al, 2020 ; Leach et al, 2021 ; Tong et al, 2017 ).…”

“…Reversion to a fetal developmental identity is a feature of WNT-independent tumorigenesis found in recent mouse models ( Han et al, 2020 ), which can be triggered by MAPK activation either via Braf -activating mutations, epithelial damage response, or stress triggered by mismatch repair deficiency ( Bommi et al, 2021 ; Leach et al, 2021 ). Critically, Braf mutations in mouse models must be accompanied by a “second hit,” such as perturbation of transforming growth factor-β (TGF-β) signaling, for tumor induction ( Han et al, 2020 ; Leach et al, 2021 ; Tong et al, 2017 ). This “second hit” may be provided by microenvironmental signals.…”

Identifying key regulators of the intestinal stem cell niche

“…Sca-1 + intestinal organoids grew as spheroids without the need for the addition of Wnt or R-spondin to culture media whereas Sca-1 − intestinal organoids had a normal budding phenotype and normal Wnt activator requirements, suggesting that Sca-1 could mark a population of reserve stem cells following some forms of intestinal injury [ 33 ]. Expression of foetal organoid enriched genes such as Anxa1 and Tacstd2/Trop are up-regulated within the regenerating intestinal epithelium [ 35 ] and differences in disease characteristics between right versus left sided colon cancer pathogenesis may be attributed to Lgr5 + versus Lgr5 − Sca-1 + ISC populations [ 36 ]. Epithelial cells in the ISC niche may therefore display region specific differences along the cephalocaudal axis leading to spatial modulation of the ISC niche.…”

Comprehensive Characterization of Transforming Growth Factor Beta Receptor 1 in Stomach Adenocarcinoma Identifies a Prognostic Signature for Predicting Clinical Outcomes and Immune Infiltrates

“…TGF‑β receptor 1 (TGFBR1), serving significant roles in the TGF‑β family, and have vital influence on many biological processes, including cell growth, reproductive capacity, and immunological reactions. 8 , 9 TGF‑β signaling plays an important role in both the growth and differentiation of tumor cells and the functional regulation of interstitial. 10 , 11 TGF-β binds to TGFBR2, forming a complex with TGFΒR1, which then phosphorylates R-SMADs, enabling the formation of a complex with SMAD4 that could enter the nucleus to regulate gene expression.…”