Role of c-Met/beta 1 integrin complex in the metastatic cascade in breast cancer

• Authors: Darryl Lau, University of California San Francisco; Harsh Wadhwa, University of California San Francisco; Sweta Sudhir, University of California San Francisco; Alexander Chih-Chieh Chang, University of California San Francisco; Sakat Jain, University of California San Francisco; Ankush Chandra, University of California San Francisco; Alan T Nguyen, University of California San Francisco; Jordan M Spatz, University of California San Francisco; Ananya Pappu, University of California San Francisco; Sumedh S Shah, University of California San Francisco; Justin Cheng, University of California San Francisco; Michael M Safaee, University of California San Francisco; Garima Yagnik, University of California San Francisco; Arman Jahangiri, Emory University; Manish K Aghi, University of California San Francisco
• Journal Title: JCI INSIGHT
• Volume: Volume 6, Number 12
• Publisher: AMER SOC CLINICAL INVESTIGATION INC | 2021-06-22
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1172/jci.insight.138928
• Subjects: Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Medicine, Research & Experimental; Research & Experimental Medicine; CELLS; EXTRAVASATION; DISSEMINATION; PATHWAYS; SURVIVAL; INVASION; GENES

Abstract

Metastases cause 90% of human cancer deaths. The metastatic cascade involves local invasion, intravasation, extravasation, metastatic site colonization, and proliferation. Although individual mediators of these processes have been investigated, interactions between these mediators remain less well defined. We previously identified a complex between receptor tyrosine kinase c-Met and β1 integrin in metastases. Using cell culture and in vivo assays, we found that c-Met/ β1 complex induction promoted intravasation and vessel wall adhesion in triple-negative breast cancer cells, but did not increase extravasation. These effects may have been driven by the ability of the c-Met/β1 complex to increase mesenchymal and stem cell characteristics. Multiplex transcriptomic analysis revealed upregulated Wnt and hedgehog pathways after c-Met/β1 complex induction. A β1 integrin point mutation that prevented binding to c-Met reduced intravasation. OS2966, a therapeutic antibody disrupting c-Met/β1 binding, decreased breast cancer cell invasion and mesenchymal gene expression. Bone-seeking breast cancer cells exhibited higher levels of c-Met/β1 complex than parental controls and preferentially adhered to tissue-specific matrix. Patient bone metastases demonstrated higher c-Met/β1 complex than brain metastases. Thus, the c-Met/β1 complex drove intravasation of triple-negative breast cancer cells and preferential affinity for bone-specific matrix. Pharmacological targeting of the complex may have prevented metastases, particularly osseous metastases.