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Cross-activating c-Met/β1 integrin complex drives metastasis and invasive resistance in cancer

Arman Jahangiri, Alan Nguyen, Ankush Chandra, Maxim K. Sidorov, Garima Yagnik, Jonathan Rick, Sung Won Han, William Chen, Patrick M. Flanigan, Dina Schneidman-Duhovny, Smita Mascharak, Michael De Lay, Brandon Imber, Catherine C. Park, Kunio Matsumoto, Kan Lu, Gabriele Bergers, Andrej Sali, William A. Weiss, and Manish K. Aghi
PNAS October 10, 2017 114 (41) E8685-E8694; published ahead of print September 26, 2017 https://doi.org/10.1073/pnas.1701821114
Arman Jahangiri
aDepartment of Neurosurgery and Brain Tumor Research Center, University of California, San Francisco, CA 94143;
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Alan Nguyen
aDepartment of Neurosurgery and Brain Tumor Research Center, University of California, San Francisco, CA 94143;
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Ankush Chandra
aDepartment of Neurosurgery and Brain Tumor Research Center, University of California, San Francisco, CA 94143;
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Maxim K. Sidorov
aDepartment of Neurosurgery and Brain Tumor Research Center, University of California, San Francisco, CA 94143;
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Garima Yagnik
aDepartment of Neurosurgery and Brain Tumor Research Center, University of California, San Francisco, CA 94143;
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Jonathan Rick
aDepartment of Neurosurgery and Brain Tumor Research Center, University of California, San Francisco, CA 94143;
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Sung Won Han
aDepartment of Neurosurgery and Brain Tumor Research Center, University of California, San Francisco, CA 94143;
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William Chen
aDepartment of Neurosurgery and Brain Tumor Research Center, University of California, San Francisco, CA 94143;
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Patrick M. Flanigan
aDepartment of Neurosurgery and Brain Tumor Research Center, University of California, San Francisco, CA 94143;
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Dina Schneidman-Duhovny
bDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143;cDepartment of Pharmaceutical Chemistry, University of California, San Francisco , CA 94143;
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Smita Mascharak
aDepartment of Neurosurgery and Brain Tumor Research Center, University of California, San Francisco, CA 94143;
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Michael De Lay
aDepartment of Neurosurgery and Brain Tumor Research Center, University of California, San Francisco, CA 94143;
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Brandon Imber
aDepartment of Neurosurgery and Brain Tumor Research Center, University of California, San Francisco, CA 94143;
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Catherine C. Park
dDepartment of Radiation Oncology and Breast Program, University of California, San Francisco, CA 94143;
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Kunio Matsumoto
eCancer Research Institute, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-8641, Japan;
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Kan Lu
aDepartment of Neurosurgery and Brain Tumor Research Center, University of California, San Francisco, CA 94143;
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Gabriele Bergers
aDepartment of Neurosurgery and Brain Tumor Research Center, University of California, San Francisco, CA 94143;
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Andrej Sali
bDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143;cDepartment of Pharmaceutical Chemistry, University of California, San Francisco , CA 94143;fCalifornia Institute for Quantitative Biosciences (QB3), University of California, San Francisco, CA 94720;
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William A. Weiss
gDepartment of Neurology, University of California, San Francisco, CA 94143
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Manish K. Aghi
aDepartment of Neurosurgery and Brain Tumor Research Center, University of California, San Francisco, CA 94143;
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  • For correspondence: manish.aghi@ucsf.edu
  1. Edited by Mina J. Bissell, E. O. Lawrence Berkeley National Laboratory, Berkeley, CA, and approved September 1, 2017 (received for review February 3, 2017)

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Significance

Invasion is a major cause of cancer mortality, as exemplified by metastatic spread of peripheral malignancies or local intracranial invasion of glioblastoma. While individual mediators of invasion are identified, functional or structural interactions between these mediators remain undefined. We identified a structural cross-activating c-Met/β1 integrin complex that promotes breast cancer metastases and invasive resistance of glioblastoma to the antiangiogenic therapy bevacizumab. We show that tumor cells adapt to their microenvironmental stressors by usurping c-Met and β1 integrin, with c-Met displacing α5 integrin from β1 integrin to form a c-Met/β1 complex with far greater fibronectin affinity than α5β1 integrin. These findings challenge conventional thinking about integrin–ligand interactions and define a molecular target for disrupting metastases or invasive oncologic resistance.

Abstract

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/β1 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/β1 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/β1 complex formation was up-regulated by hypoxia, while VEGF binding VEGFR2 sequestered c-Met and β1 integrin, preventing their binding. Complex formation promoted ligand-independent receptor activation, with integrin-linked kinase phosphorylating c-Met and crystallography revealing the c-Met/β1 complex to maintain the high-affinity β1 integrin conformation. Site-directed mutagenesis verified the necessity for c-Met/β1 binding of amino acids predicted by crystallography to mediate their extracellular interaction. Far-Western blotting and sequential immunoprecipitation revealed that c-Met displaced α5 integrin from β1 integrin, creating a complex with much greater affinity for fibronectin (FN) than α5β1. Thus, tumor cells adapt to microenvironmental stressors induced by metastases or bevacizumab by coopting receptors, which normally promote both cell migration 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/β1 complex whose ligand-independent cross-activation and robust affinity for FN drive invasive oncologic processes.

  • resistance
  • glioblastoma
  • angiogenesis
  • hypoxia
  • invasion

Footnotes

  • ↵1A.C. and M.K.S. contributed equally to this work.

  • ↵2To whom correspondence should be addressed. Email: manish.aghi{at}ucsf.edu.
  • Author contributions: A.J. and M.K.A. designed research; A.J., A.N., A.C., M.K.S., G.Y., J.R., S.W.H., W.C., P.M.F., D.S.-D., S.M., M.D.L., and B.I. performed research; A.J., D.S.-D., C.C.P., K.M., A.S., and M.K.A. contributed new reagents/analytic tools; A.J., A.N., A.C., G.Y., D.S.-D., K.M., K.L., G.B., W.A.W., and M.K.A. analyzed data; and M.K.A. wrote the paper.

  • Conflict of interest statement: M.K.A. is a member of the Scientific Advisory Board for Oncosynergy, Inc.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1701821114/-/DCSupplemental.

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c-Met/β1 integrin complex drives invasion
Arman Jahangiri, Alan Nguyen, Ankush Chandra, Maxim K. Sidorov, Garima Yagnik, Jonathan Rick, Sung Won Han, William Chen, Patrick M. Flanigan, Dina Schneidman-Duhovny, Smita Mascharak, Michael De Lay, Brandon Imber, Catherine C. Park, Kunio Matsumoto, Kan Lu, Gabriele Bergers, Andrej Sali, William A. Weiss, Manish K. Aghi
Proceedings of the National Academy of Sciences Oct 2017, 114 (41) E8685-E8694; DOI: 10.1073/pnas.1701821114

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c-Met/β1 integrin complex drives invasion
Arman Jahangiri, Alan Nguyen, Ankush Chandra, Maxim K. Sidorov, Garima Yagnik, Jonathan Rick, Sung Won Han, William Chen, Patrick M. Flanigan, Dina Schneidman-Duhovny, Smita Mascharak, Michael De Lay, Brandon Imber, Catherine C. Park, Kunio Matsumoto, Kan Lu, Gabriele Bergers, Andrej Sali, William A. Weiss, Manish K. Aghi
Proceedings of the National Academy of Sciences Oct 2017, 114 (41) E8685-E8694; DOI: 10.1073/pnas.1701821114
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