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

• Published in: Nature cell biology Vol. 20; no. 10; pp. 1203 - 1214
• Main Authors: Barnes, J. Matthew, Kaushik, Shelly, Bainer, Russell O., Sa, Jason K., Woods, Elliot C., Kai, FuiBoon, Przybyla, Laralynne, Lee, Mijeong, Lee, Hye Won, Tung, Jason C., Maller, Ori, Barrett, Alexander S., Lu, Kan V., Lakins, Jonathon N., Hansen, Kirk C., Obernier, Kirsten, Alvarez-Buylla, Arturo, Bergers, Gabriele, Phillips, Joanna J., Nam, Do-Hyun, Bertozzi, Carolyn R., Weaver, Valerie M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2018; Nature Publishing Group
• Subjects: 13; 13/1; 13/100; 13/106; 13/31; 13/89; 13/95; 14; 14/19; 14/3; 14/35; 38; 38/77; 38/89; 38/90; 59/5; 631/67; 631/80/79/1236; 631/80/79/2066; 64/110; 64/60; 82/51; 82/58; 82/80; 96; 96/109; 96/63; Animals; Antineoplastic Agents, Alkylating - therapeutic use; Biomedical and Life Sciences; Brain; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain tumors; Cancer Research; Cell Biology; Cell Survival - drug effects; Cellular signal transduction; Contractility; Developmental Biology; Extracellular matrix; Feedback loops; Feedback, Physiological - drug effects; Gene expression; Genetic aspects; Genotype & phenotype; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastomas; Gliomas; Glycocalyx; Glycocalyx - metabolism; Glycoproteins; Humans; Integrins; Integrins - metabolism; Life Sciences; Mesenchymal Stem Cells - drug effects; Mesenchymal Stem Cells - metabolism; Mesenchyme; Mice, Nude; Mortality; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Phenotypes; Stem cell research; Stem Cells; Surface Tension; Temozolomide - therapeutic use; Tension; Treatment resistance; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-018-0183-3

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. Barnes et al. report a dynamic and reciprocal crosstalk between tissue tension and glycocalyx bulkiness that promotes a mesenchymal, stem-like phenotype in GBM.