Myosin IIA suppresses glioblastoma development in a mechanically sensitive manner

Hannah S. Picariello, Rajappa S. Kenchappa, Vandana Rai, James F. Crish, Athanassios Dovas, Katarzyna Pogoda, Mariah McMahon, Emily S. Bell, Unnikrishnan Chandrasekharan, Amanda Luu, Rita West, Jan Lammerding, Peter Canoll, David J. Odde, Paul A. Janmey, Thomas Egelhoff, Steven S. Rosenfeld

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

The ability of glioblastoma to disperse through the brain contributes to its lethality and blocking this behavior has been an appealing therapeutic approach. Although a number of proinvasive signaling pathways are active in glioblastoma many are redundant so targeting one can be overcome by activating another. However these pathways converge on nonredundant components of the cytoskeleton and we have shown that inhibiting one of these-the myosin II family of cytoskeletal motors-blocks glioblastoma invasion even with simultaneous activation of multiple upstream promigratory pathways. Myosin IIA and IIB are the most prevalent isoforms of myosin II in glioblastoma and we now show that codeleting these myosins markedly impairs tumorigenesis and significantly prolongs survival in a rodent model of this disease. However while targeting just myosin IIA also impairs tumor invasion it surprisingly increases tumor proliferation in a manner that depends on environmental mechanics. On soft surfaces myosin IIA deletion enhances ERK1/2 activity while on stiff surfaces it enhances the activity of NFκB not only in glioblastoma but in triple-negative breast carcinoma and normal keratinocytes as well. We conclude myosin IIA suppresses tumorigenesis in at least two ways that are modulated by the mechanics of the tumor and its stroma. Our results also suggest that inhibiting tumor invasion can enhance tumor proliferation and that effective therapy requires targeting cellular components that drive both proliferation and invasion simultaneously.

Original languageEnglish (US)
Pages (from-to)15550-15559
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number31
DOIs
StatePublished - Jul 30 2019

Keywords

  • Glioblastoma
  • Invasion
  • Myosin
  • Signaling

ASJC Scopus subject areas

  • General

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  • Cite this

    Picariello, H. S., Kenchappa, R. S., Rai, V., Crish, J. F., Dovas, A., Pogoda, K., McMahon, M., Bell, E. S., Chandrasekharan, U., Luu, A., West, R., Lammerding, J., Canoll, P., Odde, D. J., Janmey, P. A., Egelhoff, T., & Rosenfeld, S. S. (2019). Myosin IIA suppresses glioblastoma development in a mechanically sensitive manner. Proceedings of the National Academy of Sciences of the United States of America, 116(31), 15550-15559. https://doi.org/10.1073/pnas.1902847116