Remodeling of tumor microenvironment by extracellular matrix protein 1a differentially regulates ovarian cancer metastasis

Abstract

We previously reported that extracellular matrix protein 1 isoform a (ECM1a) promotes epithelial ovarian cancer (EOC) through autocrine signaling by binding to cell surface receptors αXβ2. However, the role of ECM1a as a secretory molecule in the tumor microenvironment is rarely reported. In this study, we constructed murine Ecm1-knockout mice and human ECM1a-knockin mice and further generated orthotopic or peritoneal xenograft tumor models to mimic the different metastatic stages of EOC. We show that ECM1a induces oncogenic metastasis of orthotopic xenograft tumors, but inhibits early-metastasis of peritoneal xenograft tumors. ECM1a remodels extracellular matrices (ECM) and promotes remote metastases by recruiting and transforming bone marrow mesenchymal stem cells (BMSCs) into platelet-derived growth factor receptor beta (PDGFRβ⁺) cancer-associated fibroblasts (CAFs) and facilitating the secretion of angiopoietin-like protein 2 (ANGPTL2). Competing with ECM1a, ANGPTL2 also binds to integrin αX through the P1/P2 peptides, resulting in negative effects on BMSC differentiation. Collectively, this study reveals the dual functions of ECM1a in remodeling of TME during tumor progression, emphasizing the complexity of EOC phenotypic heterogeneity and metastasis.

Keywords: Angiopoietin-like protein 2 (ANGPTL2); Cancer associated fibroblasts (CAFs); Epithelial ovarian cancer (EOC); Extracellular matrix protein 1 (ECM1); Extracellular matrix remodeling (ECM remodeling).