Collagen-rich omentum is a premetastatic niche for integrin α2-mediated peritoneal metastasis.

Yen-Lin Huang,Manuela Estermann,Natalie Rimmer,Andreas Schötzau,Viola Heinzelmann-Schwarz,Francis Jacob,Cécile Cumin,Diego Calabrese,Leonor David,Claudia Lengerke,Danilo Ritz,Tatjana Vlajnic,Dedy Septiadi,Mónica Núñez López,Ricardo Coelho,Barbara Rothen-Rutishauser,Martina Konantz,André Fedier,Ching-Yeu Liang

doi:10.7554/elife.59442

Abstract

The extracellular matrix (ECM) plays critical roles in tumor progression and metastasis. However, the contribution of ECM proteins to early metastatic onset in the peritoneal cavity remains unexplored. Here, we suggest a new route of metastasis through the interaction of integrin alpha 2 (ITGA2) with collagens enriched in the tumor coinciding with poor outcome in patients with ovarian cancer. Using multiple gene-edited cell lines and patient-derived samples, we demonstrate that ITGA2 triggers cancer cell adhesion to collagen, promotes cell migration, anoikis resistance, mesothelial clearance, and peritoneal metastasis in vitro and in vivo. Mechanistically, phosphoproteomics identify an ITGA2-dependent phosphorylation of focal adhesion kinase and mitogen-activated protein kinase pathway leading to enhanced oncogenic properties. Consequently, specific inhibition of ITGA2-mediated cancer cell-collagen interaction or targeting focal adhesion signaling may present an opportunity for therapeutic intervention of metastatic spread in ovarian cancer.

Highlights

Peritoneal metastasis is the leading cause of mortality in epithelial ovarian cancer (EOC) and results in a 17–39% 5 year survival rate due to the majority of patients being diagnosed at advanced stage of disease (>75%, FIGO stage III/IV) (Halkia et al, 2012; Vaughan et al, 2011)
We demonstrate that the collagen-binding integrin a2 (ITGA2) on EOC cells is required for direct and selective cell adhesion to various collagens which are enriched in the omentum
Using multiple cell lines and patient-derived samples, we provide functional evidence that integrin alpha 2 (ITGA2) promotes cancer cell adhesion, anoikis resistance, and tumor spheroid-mediated mesothelial clearance in vitro as well as peritoneal metastasis in vivo. (Phospho-)proteomics reveal that ITGA2dependent signaling is transduced by phosphorylation of focal adhesion kinase and mitogen-activated protein kinase (MAPK) signaling pathway

Summary

Introduction

Peritoneal metastasis is the leading cause of mortality in epithelial ovarian cancer (EOC) and results in a 17–39% 5 year survival rate due to the majority of patients being diagnosed at advanced stage of disease (>75%, FIGO stage III/IV) (Halkia et al, 2012; Vaughan et al, 2011). Ascites-derived tumor cells (ATCs) contribute to an invasive and chemo-resistant cell population with high potential to form metastasis (Kipps et al, 2013; Lawrenson et al, 2011; Sodek et al, 2009). Emerging studies highlight the dynamic interplay between malignant, stromal and immune cells in the premetastatic niche promoting cancer cell adhesion, invasion, and progression leading to peritoneal metastasis. Altered collagen organization influences tissue mechanics and compromises drug delivery (Loeffler et al, 2006) contributes to the poor response to chemotherapy in EOC patients (Jazaeri et al, 2005). Despite solid evidence on the role of collagens in the already established tumor microenvironment, their contribution at the metastatic niche of early peritoneal dissemination remains largely unexplored

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