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

• Type of Material: Article
• 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
• Language: English
• Date: 2021-06-22
• Publisher: AMER SOC CLINICAL INVESTIGATION INC
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Lau et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1172/jci.insight.138928
• Title of Journal or Parent Work: JCI INSIGHT
• Volume: 6
• Issue: 12
• Grant/Funding Information: Work was supported by funding to MKA’s lab from the NIH (grants 1R01CA227136 and 2R01NS079697). DL was supported by a CTSI TL1 postdoctoral fellowship and the Neurosurgery Research Education Foundation.; AJ was an HHMI fellow and was supported by the NIH (grant 1F31CA203372-01). AC and SSS were HHMI fellows. JS was supported by the UCSF Yearlong Inquiry Program.
• Keywords: Research & Experimental Medicine; GENES; CELLS; DISSEMINATION; SURVIVAL; PATHWAYS; Science & Technology; Life Sciences & Biomedicine; EXTRAVASATION; Medicine, Research & Experimental; INVASION
• Research Categories: Health Sciences, Medicine and Surgery

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.