PDGFR-induced autocrine SDF-1 signaling in cancer cells promotes metastasis in advanced skin carcinoma

Abstract

Advanced and undifferentiated skin squamous cell carcinomas (SCCs) exhibit aggressive growth and enhanced metastasis capability, which is associated in mice with an expansion of the cancer stem-like cell (CSC) population and with changes in the regulatory mechanisms that control the proliferation and invasion of these cells. Indeed, autocrine activation of PDGFRα induces CSC invasion and promotes distant metastasis in advanced SCCs. However, the mechanisms involved in this process were unclear. Here, we show that CSCs of mouse advanced SCCs (L-CSCs) express CXCR4 and CXCR7, both receptors of SDF-1. PDGFRα signaling induces SDF-1 expression and secretion, and the autocrine activation of this pathway in L-CSCs. Autocrine SDF-1/CXCR4 signaling induces L-CSC proliferation and survival, and mediates PDGFRα-induced invasion, promoting in vivo lung metastasis. Validation of these findings in patient samples of skin SCCs shows a strong correlation between the expression of SDF1, PDGFRA, and PDGFRB, which is upregulated, along CXCR4 in tumor cells of advanced SCCs. Furthermore, PDGFR regulates SDF-1 expression and inhibition of SDF-1/CXCR4 and PDGFR pathways blocks distant metastasis of human PD/S-SCCs. Our results indicate that functional crosstalk between PDGFR/SDF-1 signaling regulates tumor cell invasion and metastasis in human and mouse advanced SCCs, and suggest that CXCR4 and/or PDGFR inhibitors could be used to block metastasis of these aggressive tumors.

The CXCL12 Crossroads in Cancer Stem Cells and Their Niche

“…These CSCs express Cxcr4, Cxcr7, and secrete Cxcl12. In contrast to what had been previously described by Faber et al, this activated cell proliferation and survival and promoted lung metastasis [ 139 ]. The authors validated their findings in patient samples and reported the upregulation of PDGFRα, PDGFRβ, and CXCL12 in tumor cells.…”

Cutaneous Squamous Cell Carcinoma: From Biology to Therapy

“…Recent studies demonstrate that the CSCC tumor microenvironment is enriched in cancer-associated fibroblasts (CAFs) [65] and tumor-associated macrophages [66]. Tumor stromal cells are implicated in the invasion, metastases, tumor progression, and response to chemotherapy [67,68]. Cellular and molecular components of the tumor microenvironment are of great importance in the effect of immunotherapy, as described below.…”

The Role of Tyrosine Kinases as a Critical Prognostic Parameter and Its Targeted Therapies in Ewing Sarcoma

“…Functional crosstalk between PDGF-BB/PDGFR and stromal-derived growth factor 1α (SDF-1α)/C-X-C motif chemokine receptor 4 (CXCR4) requires enhanced cancer tumorigenesis and metastasis. Autocrine activation of PDGFRα induced tumorigenesis and metastasis in advanced skin squamous cell carcinomas (SCCs) via upregulation and secretion of SDF-1α, and then SDF-1/CXCR4 induced PDGFR-induced tumor cell invasion and metastasis ( Bernat-Peguera et al, 2019 ). Furthermore, PDGFRβ inhibitors inhibited SDF-1α-induced chemotaxis in glioblastoma ( Sciaccaluga et al, 2013 ), and PDGF-BB induced CXCR4 and CXCR7 expression in pericytes ( Xiang et al, 2019 ).…”