CMS1_Mouse_Model_Development. CMS1_Mouse_Model_Development

Within the Sansom lab we are developing a suite of mouse models of colorectal cancer which we are positioning against patient samples and molecular subtypes (CMS and CRIS subtypes). This specific sub-strand of work is aiming to develop CMS1 like mouse models. CMS1 tumours are associated with Braf mutation, mismatch repair deficiency and microsatellite instability (commonly secondary to MLH1 methylation). As a result of susceptibility because of the presence of a microsatellite in their DNA sequence a number of other mutations are commonly associated with mismatch repair deficient tumours also, particularly TGFbR2. A further mutation associated with CMS1, mismatch repair deficient tumours is HUWE which we believe synergises in this context due to the induction of DNA damage. We have developed models that show that the specific combination of Braf and TGFbR mutations drive tumours in the proximal colon of mice, the equivalent of right-sided tumours in patients, for which CMS1 tumours are overrepresented. Interestingly these tumours are microbiome dependent and express a fetal signature. We have also developed the first conditional MLH1 knockout mouse which in combination with VillinCreER drives intestinal tumours with profound T cell infiltration. Because the mouse lacks a microsatellite in its’ TGFBR2 gene we have also developed mouse models in which we combine combinations of Braf, MLH1-/-, and TGFbR2-/-. Furthermore due to the synergy between HUWE mutation and mismatch repair deficiency we have also developed combinations of Braf, MLH1-/-, HUWE-/- models, all of which develop tumours with significantly shortened latency than MLH1-/- alone.