Epithelial TGFβ activation engages growth-factor signalling to circumvent cell death and drive intestinal tumorigenesis with aggressive features.

The pro-tumourigenic role of epithelial TGFβ in colorectal cancer (CRC) is controversial. Here we identify a cohort of aggressive ‘bad acting’ early-stage (T1) disseminating tumours characterised by high cell-intrinsic TGFβ signalling emanating from the epithelium, rather than the stroma. To address its functional significance, we activated TGFβ signalling in the murine intestinal epithelium either alone or in concert with the common tumour suppressive and oncogenic mutations found in CRC, namely Apc and Kras. Consistent with previous studies, we found that activation of TGFβ rapidly induced apoptosis in Apc-mutant intestine and completely killed Apc-mutant organoids. However, in the presence of both Apc and Kras mutation, activation of TGFβ within the epithelium rampantly accelerates tumourigenesis. Importantly, the transcriptional signatures derived from these mice overlapped with the “bad acting” T1 human tumours and this signalling could also predict recurrence in stage II CRC. Mechanistically, the activation of intrinsic TGFβ induced expression of a growth-factor signalling module containing EGFR that synergised with Apc and Kras to drive marked activation of MAPK signalling. Importantly, inhibition of MEK and/or EGFR suppressed the acceleration conferred by TGFβ, even in Kras-mutant cells, which are refractory to MEK/EGFR inhibition in the absence of epithelial TGFβ. Together, we identify both a determinant of early dissemination and a potential vulnerability for tumours with these “born-to-be-bad” traits.

This repository contains source code used to generate Figure 1, 6 and Extended Data Figure 1 and 7 in Dustin J. Flanagan, Raheleh Amirkhah, David F. Vincent, et al. (submitted, not published yet).