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Probing Myosin Ensemble Mechanics in Actin Filament Bundles Using Optical Tweezers
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Myosin IIA suppresses glioblastoma development in a mechanically sensitive manner

Hannah S Picariello1, Rajappa S Kenchappa2, Vandana Rai1

  • 1Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.

Proceedings of the National Academy of Sciences of the United States of America
|June 26, 2019
PubMed

Insights

Targeting myosin II motors blocks glioblastoma invasion. Codeleting myosin IIA and IIB impairs tumor growth and prolongs survival, but targeting myosin IIA alone can increase proliferation depending on mechanics.

Area of Science:

  • Oncology
  • Cell Biology
  • Biophysics

Background:

  • Glioblastoma's lethality stems from its ability to disperse through the brain.
  • Targeting proinvasive pathways is challenging due to redundancy, necessitating focus on nonredundant downstream effectors like the cytoskeleton.
  • Myosin II motors are key cytoskeletal components regulating cell motility.

Purpose of the Study:

  • To investigate the role of myosin II isoforms (IIA and IIB) in glioblastoma invasion and tumorigenesis.
  • To determine the impact of targeting myosin II on glioblastoma proliferation and survival.
  • To explore the influence of environmental mechanics on myosin II-mediated signaling pathways.

Main Methods:

  • Genetic codeletion of myosin IIA and IIB in a rodent glioblastoma model.
  • Inhibition of specific myosin II isoforms (myosin IIA) in glioblastoma.
  • Assessment of tumor invasion, proliferation, and survival rates.
  • Analysis of signaling pathway activation (ERK1/2, NFκB) under varying substrate stiffness.

Main Results:

  • Codeletion of myosin IIA and IIB significantly impaired glioblastoma tumorigenesis and prolonged survival.
  • Inhibition of myosin IIA alone reduced invasion but unexpectedly increased proliferation.
  • Myosin IIA deletion modulated ERK1/2 and NFκB activity based on environmental stiffness in glioblastoma, breast cancer, and keratinocytes.

Conclusions:

  • Myosin IIA plays a dual role in suppressing tumorigenesis, modulated by mechanical cues from the tumor microenvironment.
  • Therapeutic strategies must simultaneously target both proliferation and invasion pathways for effective glioblastoma treatment.
  • Understanding the interplay between cytoskeletal mechanics and signaling is crucial for developing novel cancer therapies.
Keywords:
glioblastomainvasionmyosinsignaling

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