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

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) wit...

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Published in:eLife 2020-10, Vol.9
Main Authors: Huang, Yen-Lin, Liang, Ching-Yeu, Ritz, Danilo, Coelho, Ricardo, Septiadi, Dedy, Estermann, Manuela, Cumin, Cécile, Rimmer, Natalie, Schötzau, Andreas, Núñez López, Mónica, Fedier, André, Konantz, Martina, Vlajnic, Tatjana, Calabrese, Diego, Lengerke, Claudia, David, Leonor, Rothen-Rutishauser, Barbara, Jacob, Francis, Heinzelmann-Schwarz, Viola
Format: Article
Language:English
Subjects:
Animals
Cancer Biology
Carcinoma, Ovarian Epithelial - metabolism
Cell adhesion
Cell Biology
Cell Line, Tumor
Collagen
Collagen - metabolism
Female
focal adhesion kinase
integrin alpah 2
Integrin alpha2 - metabolism
Mice
Neoplasm Metastasis - physiopathology
omentum
Omentum - physiopathology
Peritoneal metastasis
Peritoneum - physiopathology
Zebrafish
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Summary: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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.59442