Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 41, Pages E8685-E8694Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1701821114
Keywords
resistance; glioblastoma; angiogenesis; hypoxia; invasion
Categories
Funding
- American Brain Tumor Association
- James S. McDonnell Foundation
- American Cancer Society
- NIH [5K02NS64167, 1 R01 NS079697, 1F31CA203372-01]
- UCSF Brain Tumor Specialized Program of Research Excellence (SPORE) [CA097257]
- UCSF
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The molecular underpinnings of invasion, a hallmark of cancer, have been defined in terms of individual mediators but crucial interactions between these mediators remain undefined. In xenograft models and patient specimens, we identified a c-Met/beta 1 integrin complex that formed during significant invasive oncologic processes: breast cancer metastases and glioblastoma invasive resistance to antiangiogenic VEGF neutralizing antibody, bevacizumab. Inducing c-Met/beta 1 complex formation through an engineered inducible heterodimerization system promoted features crucial to overcoming stressors during metastases or antiangiogenic therapy: migration in the primary site, survival under hypoxia, and extravasation out of circulation. c-Met/beta 1 complex formation was up-regulated by hypoxia, while VEGF binding VEGFR2 sequestered c-Met and beta 1 integrin, preventing their binding. Complex formation promoted ligand-independent receptor activation, with integrin-linked kinase phosphorylating c-Met and crystallography revealing the c-Met/beta 1 complex to maintain the high-affinity beta 1 integrin conformation. Site-directed mutagenesis verified the necessity for c-Met/beta 1 binding of amino acids predicted by crystallography to mediate their extracellular interaction. Far-Western blotting and sequential immunoprecipitation revealed that c-Met displaced alpha 5 integrin from beta 1 integrin, creating a complex with much greater affinity for fibronectin (FN) than alpha 5 beta 1. Thus, tumor cells adapt to microenvironmental stressors induced bymetastases or bevacizumab by coopting receptors, which normally promote both cellmigration modes: chemotaxis, movement toward concentrations of environmental chemoattractants, and haptotaxis, movement controlled by the relative strengths of peripheral adhesions. Tumor cells then redirect these receptors away from their conventional binding partners, forming a powerful structural c-Met/beta 1 complex whose ligand-independent cross-activation and robust affinity for FN drive invasive oncologic processes.
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