|Title||Stromal SOX2 Upregulation Promotes Tumorigenesis through the Generation of a SFRP1/2-Expressing Cancer-Associated Fibroblast Population.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Kasashima H, Duran A, Martinez-Ordoñez A, Nakanishi Y, Kinoshita H, Linares JF, Reina-Campos M, Kudo Y, L'Hermitte A, Yashiro M, Ohira M, Bao F, Tauriello DVF, Batlle E, Diaz-Meco MT, Moscat J|
|Date Published||2021 01 11|
|Keywords||Animals, beta Catenin, Cancer-Associated Fibroblasts, Carcinogenesis, Cell Line, Tumor, Cell Movement, Colorectal Neoplasms, Disease Progression, Extracellular Matrix, Female, Humans, Intercellular Signaling Peptides and Proteins, Membrane Proteins, Mice, Mice, Inbred BALB C, Mice, Knockout, Neoplasm Invasiveness, Organoids, Protein Binding, Protein Kinase C, Recurrence, RNA-Seq, Signal Transduction, Single-Cell Analysis, SOXB1 Transcription Factors, Up-Regulation|
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.
|Alternate Journal||Dev Cell|
|PubMed Central ID||PMC7856011|
|Grant List||R01 DK108743 / DK / NIDDK NIH HHS / United States |
R01 CA218254 / CA / NCI NIH HHS / United States
R01 CA211794 / CA / NCI NIH HHS / United States
P30 CA030199 / CA / NCI NIH HHS / United States
R01 CA207177 / CA / NCI NIH HHS / United States
R01 CA246765 / CA / NCI NIH HHS / United States
Jorge Moscat, Ph.D. Juan Francisco Linares Rodriguez, Ph.D. Maria Diaz-Meco Conde, Ph.D.