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DOI: 10.1055/s-0040-1718145
Integrin α2-collagen interaction promotes ovarian cancer metastasis
Objective The contribution of the extracellular matrix (ECM) in the pre-metastatic niche for early steps of cancer cell metastasis remain largely unexplored. Therefore,we aim to study the interplay between integrin-ECM in mediating ovarian cancer cell metastasis.
Methods CRISPR-Cas9, ECM adhesion assay, mesothelial clearance, in vivo xenograft, tissue microarray, proteomics.
Results We describe a unique expression of collagens in normal omentum, representing the most important metastatic site in advanced epithelial ovarian cancer. Elevated levels of various collagens in omental metastatic disease coincides with poor outcome in large transcriptomic datasets. We also identified that collagen-binding receptor, integrin alpha 2 (ITGA2) is highly abundant in matched patient-derived tissues and ascites. ITGA2-collagen mediated cancer cell adhesion is reversible using gene-edited strategy. Moreover, ITGA2 drives directed cell migration, anoikis resistance and mesothelial clearance in vitro and promotes metastasis in vivo. The patient-derived ex vivo cultures can be pharmacologically inhibited. Mechanistically, loss of ITGA2-dependent signaling downregulates the focal adhesion kinase signaling. Specific inhibition of ITGA2-mediated cancer cell-collagen adhesion by TC-I-15 or Defactinib may present an opportunity for therapeutic intervention of metastatic spread in ovarian cancer.
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Publication History
Article published online:
07 October 2020
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