Kasashima et al, Developmental Cell 2020

Cancer-associated fibroblasts (CAFs) promote tumor malignancy, but the precise
transcriptional mechanisms regulating the acquisition of the CAF phenotype are not
well understood. We show that the upregulation of SOX2 is central to this process,
which is repressed by protein kinase Cζ (PKC ζ ). PKC ζ deficiency activates the
reprogramming of colonic fibroblasts to generate a predominant SOX2-dependent CAF
population expressing the WNT regulator Sfrp2 as its top biomarker. SOX2 directly
binds the Sfrp1/2 promoters, and the inactivation of Sox2 or Sfrp1 / 2 in CAFs impaired
the induction of migration and invasion of colon cancer cells, as well as their
tumorigenicity in vivo. Importantly, recurrence-free and overall survival of colorectal
cancer (CRC) patients negatively correlates with stromal PKC ζ levels. Also, SOX2
expression in the stroma is associated with CRC T invasion and worse prognosis of
recurrence-free survival. Therefore, the PKC ζ -SOX2 axis emerges as a critical step in
the control of CAF pro-tumorigenic potential.