Molecular mechanisms driving mesenchymal colorectal cancer

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SUMMARY A stem-mesenchymal phenotype of the tumor epithelium, and its associated immunosuppressive and desmoplastic stroma, are fundamental characteristics of the most aggressive and poor survival type of colorectal cancer CRC. However, the molecular and cellular mechanisms driving this process are still far from clear. This proposal stems from a series of recently published and unpublished observations in my laboratory that identify the two atypical PKCs (aPKC; PKC and PKC/) as novel tumor suppressors acting in concert to prevent this aggressive form of CRC. Thus, the simultaneous loss of both aPKCs in the intestinal epithelium (in a new DKOIEC mouse line) results in highly mesenchymal adenocarcinomas with a reactive and strongly immunosuppressed stroma. Both aPKCs are significantly downregulated in mesenchymal/stromal/ immunosuppressive CRC human patients who have the most unfavorable prognosis. Our unpublished preliminary data demonstrate that intestinal epithelial cells (IECs) deficient in PKC/ (or both aPKCs) upregulate the stem cell receptor CD44, concomitant with the downregulation of Lgr5+ intestinal stem cells, suggesting the appearance of a new type of tumor initiating cells (TICs). Inhibition of CD44+ in tumor organoids demonstrate its requirement for growth and supports its physiopathological relevance. Consistently, inhibition of one of the key CD44 stromal ligands (hyaluronan) in vivo abrogates the mesenchymal phenotype of DKOIEC tumors inhibiting the immunosuppressive response and restoring immunosurveillance. We hypothesize that the upregulation of a new type of CD44+/Lgr5- TICs by the loss of PKC/ is central in the development of the aggressive type of CRC. The upregulation of the MAP kinase cascades, together with the identification, in a series of unbiassed approaches, of the transcription factor KLF4 as a potential critical intermediary between PKC/ and CD44 expression, led us to hypothesize that the activation of ERK/JNK by PKC/ deficiency triggers AP1 and, concurrently, induces the degradation of KLF4; both actions cooperate to drive CD44 expression and the mesenchymal phenotype of very aggressive CRC. Therefore, in this proposal, we will determine the role of CD44 in the aggressive/mesenchymal type of CRC (Aim 1), as well as the molecular mechanisms whereby PKC/ regulates CD44 expression and function in this process (Aim 2). The successful completion of the proposed studies will create a new paradigm of significance and impact that will contribute to a more comprehensive understanding of the mechanisms driving the poor prognosis mesenchymal type of CRC, which will be key for the design of new therapeutic targets for this type of aggressive neoplasia.