Stromal SOX2 Upregulation Promotes Tumorigenesis through the Generation of a SFRP1/2-Expressing Cancer-Associated Fibroblast Population. Academic Article uri icon

Overview

abstract

  • 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 (PKCζ). PKCζ 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 PKCζ levels. Also, SOX2 expression in the stroma is associated with CRC T invasion and worse prognosis of recurrence-free survival. Therefore, the PKCζ-SOX2 axis emerges as a critical step in the control of CAF pro-tumorigenic potential.

publication date

  • November 17, 2020

Research

keywords

  • Cancer-Associated Fibroblasts
  • Carcinogenesis
  • Colorectal Neoplasms
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Protein Kinase C
  • SOXB1 Transcription Factors

Identity

PubMed Central ID

  • PMC7856011

Scopus Document Identifier

  • 85097223720

Digital Object Identifier (DOI)

  • 10.1016/j.devcel.2020.10.014

PubMed ID

  • 33207226

Additional Document Info

volume

  • 56

issue

  • 1