Stromal SOX2 Upregulation Promotes Tumorigenesis through the Generation of a SFRP1/2-Expressing Cancer-Associated Fibroblast Population

• Published in: Developmental cell Vol. 56; no. 1; pp. 95 - 110.e10
• Main Authors: Kasashima, Hiroaki, Duran, Angeles, Martinez-Ordoñez, Anxo, Nakanishi, Yuki, Kinoshita, Hiroto, Linares, Juan F., Reina-Campos, Miguel, Kudo, Yotaro, L’Hermitte, Antoine, Yashiro, Masakazu, Ohira, Masaichi, Bao, Fei, Tauriello, Daniele V.F., Batlle, Eduard, Diaz-Meco, Maria T., Moscat, Jorge
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.01.2021
• Subjects: Animals; atypical PKCs; beta Catenin - genetics; beta Catenin - metabolism; cancer-associated fibroblasts; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; Carcinogenesis - genetics; Carcinogenesis - metabolism; Cell Line, Tumor; Cell Movement - genetics; CMS4; colorectal cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Disease Progression; Extracellular Matrix - genetics; Extracellular Matrix - metabolism; Extracellular Matrix - pathology; Female; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; metastasis; Mice; Mice, Inbred BALB C; Mice, Knockout; Neoplasm Invasiveness - genetics; Organoids - metabolism; Organoids - pathology; PKCz; Protein Binding; Protein Kinase C - deficiency; Protein Kinase C - genetics; Protein Kinase C - metabolism; Recurrence; RNA-Seq; SFRP; Signal Transduction - genetics; Signal Transduction - immunology; Single-Cell Analysis; SOX2; SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism; stroma; TGFβ; Up-Regulation; SOX2; cancer-associated fibroblasts; colorectal cancer; CMS4; metastasis; stroma; PKCz; SFRP; atypical PKCs; TGFβ
• ISSN: 1534-5807; 1878-1551; 1878-1551
• DOI: 10.1016/j.devcel.2020.10.014

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. [Display omitted] •PKCζ is lost in the stroma of poor-prognosis mesenchymal human CMS4 CRC•Stromal loss of PKCζ upregulates SOX2 to promote the CAF phenotype•Selective deletion of PKCζ in fibroblast activates the SOX2/SFRP1/2 axis in vivo•Stromal SOX2 negatively correlates with PKCζ and predicts poor survival in CRC Kasashima et al. describe a molecular mechanism whereby the loss of PKCζ in the stroma upregulates SOX2 to activate the reprogramming of colonic fibroblasts generating a SFRP1/2-expressing CAF population. This population supports epithelial tumor progression, revealing vulnerabilities in mesenchymal CMS4 colorectal cancer.