Stromal upregulation of SOX2 promotes tumorigenesis through the generation of a SFRP1/2-expressing cancer-associated fibroblast population [Quant-seq]

Although how CAFs impact the tumor epithelium is being progressively unveiled, transcriptional processes of lineage plasticity in fibroblasts govern the acquisition of the CAF phenotype are much less understood. Here we show that the upregulation of SOX2 is a critical step in this process, which is negatively regulated by the atypical protein kinase (aPKC) PKCz. We demonstrate that the loss of PKCz is essential for the acquisition of the CAF phenotype and for the induction of the desmoplastic and more aggressive phenotype of intestinal tumors in a SOX2-dependent manner. Furthermore, we show here that the loss of PKCz drives the reprogramming of colon stromal fibroblasts into two different subpopulations that express either the Wnt regulators Sfrp1/2 or osteopontin, both ligands positively impinging into the mesenchymal and stem cell activation programs. Overall design: WT sgScr, Prkcz-/- sgScr and Prkcz-/- sgSox2 colon fibroblasts were profiled in four biological replicates under normal conditions.