CD38 in cancer-associated fibroblasts promotes pro-tumoral activity

Abstract

AbstractPrimary and metastatic melanoma progression are supported by a local microenvironment comprising, inter alia, of cancer-associated fibroblasts (CAFs). We previously reported in orthotropic/syngeneic mouse models that the stromal ectoenzyme CD38 participates in melanoma growth and metastasis. The results presented here suggest that CD38 is a novel regulator of CAFs' pro-tumorigenic functions. Orthotopic co-implantation of CD38 deficient fibroblasts and B16F10 melanoma cells limited tumor size, compared with CD38-expressing fibroblasts. Intrinsically, CAF-CD38 promoted migration of primary fibroblasts toward melanoma cells. Further, in vitro paracrine effects of CAF-CD38 fostered tumor cell migration and invasion as well as endothelial cell tube formation. Mechanistically, we report that CAF-CD38 drives the protein expression of an angiogenic/pro-metastatic signature, which includes VEGF-A, FGF-2, CXCL-12, MMP-9, and HGF. Data suggest that CAF-CD38 fosters tumorigenesis by enabling the production of pro-tumoral factors that promote cell invasion, migration, and angiogenesis.This study reports novel pro-tumorigenic functions for CD38 in cancer associated fibroblasts (CAFs). In vivo, CAF CD38 promotes melanoma expansion. Mechanistically, CD38 enhances CAF migration towards cancer cells as well as tumor cell migration and invasion. Further, CD38 enables de novo endothelial tube formation by upregulating angiogenic transcripts and pro-angiogenic secreted factors.