A tension-mediated glycocalyx–integrin feedback loop promotes mesenchymal-like glioblastoma

J. Matthew Barnes, Shelly Kaushik, Russell O. Bainer, Jason K. Sa, Elliot C. Woods, Fui Boon Kai, Laralynne Przybyla, Mijeong Lee, Hye Won Lee, Jason C. Tung, Ori Maller, Alexander S. Barrett, Kan V. Lu, Jonathon N. Lakins, Kirk C. Hansen, Kirsten Obernier, Arturo Alvarez-Buylla, Gabriele Bergers, Joanna J. Phillips, Do Hyun NamCarolyn R. Bertozzi, Valerie M. Weaver

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

Abstract

Glioblastoma multiforme (GBMs) are recurrent lethal brain tumours. Recurrent GBMs often exhibit mesenchymal, stem-like phenotypes that could explain their resistance to therapy. Analyses revealed that recurrent GBMs have increased tension and express high levels of glycoproteins that increase the bulkiness of the glycocalyx. Studies showed that a bulky glycocalyx potentiates integrin mechanosignalling and tissue tension and promotes a mesenchymal, stem-like phenotype in GBMs. Gain- and loss-of-function studies implicated integrin mechanosignalling as an inducer of GBM growth, survival, invasion and treatment resistance, and a mesenchymal, stem-like phenotype. Mesenchymal-like GBMs were highly contractile and expressed elevated levels of glycoproteins that expanded their glycocalyx, and they were surrounded by a stiff extracellular matrix that potentiated integrin mechanosignalling. Our findings suggest that there is a dynamic and reciprocal link between integrin mechanosignalling and a bulky glycocalyx, implying a causal link towards a mesenchymal, stem-like phenotype in GBMs. Strategies to ameliorate GBM tissue tension offer a therapeutic approach to reduce mortality due to GBM.

Original languageEnglish
Pages (from-to)1203-1214
Number of pages12
JournalNature Cell Biology
Volume20
Issue number10
DOIs
Publication statusPublished - 2018 Oct 1
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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