Jorge Moscat

Colorectal cancer (CRC) is a major cause of cancer mortality worldwide, with poor survival rates despite improvements in systemic treatment.  An emerging notion in the CRC field is that a stem-mesenchymal phenotype of the tumor epithelium, together with an immunosuppressive and desmoplastic stroma, predicts adverse outcomes in CRC patients better than the presence of prevalent mutations. Instead, key features of the tumor microenvironment, such as lack of T cell infiltration, increased immunosuppression, and a highly mesenchymal phenotype with desmoplastic stroma, predict adverse outcomes in CRC patients. Indeed, these are defining characteristics of the poor prognosis CMS4 subtypes, according to the most recent classifications of transcriptomic subtypes of CRC, which account for approximately 30% of all CRC cases. Therefore, considering their poor prognosis and resistance to therapy, the identification of the molecular mechanisms central to the acquisition of the mesenchymal phenotype of CRC tumors and establishing how that drives their aggressiveness is a fundamental question whose resolution will contribute to a better understanding of the etiopathogenesis of this type of poor-prognosis CRC.  

Figure 1

Our laboratory recently found that the expression of atypical protein kinase Cs, PKCz, and PKCl/i, is reduced in human mesenchymal CRC with serrated carcinoma and desmoplasia features that transcriptionally conform to the CMS4 subtype. The simultaneous inactivation of both kinases in the mouse intestinal epithelium results in spontaneous serrated tumorigenesis that progresses to advanced cancer with a strongly reactive and immunosuppressive stroma. Using this unique mesenchymal CRC mouse model and interrogation of human samples and datasets, we investigate two major questions: (1) what are the mechanisms of initiation that control and promote preneoplasia? and (2) what mechanisms drive therapy resistance and liver metastasis?  

Figure 2