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 Nam; Carolyn R. Bertozzi; Valerie M. Weaver

doi:10.1038/s41556-018-0183-3

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 journal › Article › peer-review

106 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 language	English
Pages (from-to)	1203-1214
Number of pages	12
Journal	Nature Cell Biology
Volume	20
Issue number	10
DOIs	https://doi.org/10.1038/s41556-018-0183-3
Publication status	Published - 2018 Oct 1
Externally published	Yes

Bibliographical note

Funding Information:
We thank W. Weiss (UCSF) for the S100β-vErb:p53+/– mice and M. Paszek (Cornell University) for helpful discussions. Animal handling and tissue preparation was supported by L. Korets and N. Korets (UCSF). This work was supported by the following grants: US National Institutes of Health NCI R01 grants CA138818-01A1, CA192914-01, CA174929-01 and CA085482 (V.M.W.); U01 grant CA202241 (V.M.W. and F.K.); U54 grant CA163155 (V.M.W.); Ruth Kirschstein NRSA F32 CA174319 (J.M.B.); UCSF Brain Tumor Research Program T32 CA151022 (J.M.B.); NHLBI T32 HL007544 (J.C.T.); UCSF Brain Tumor SPORE Tissue Core NIH/NCI P50 CA097257 (J.J.P.); NIH 1U01CA168878 (J.J.P); NIH/NINDS R01 NS081117 (J.J.P.); CIRM grant RB5-07409 (V.M.W.); CIRM training grant TG2-01153 (L.P.); and NCI R01 CA227942 (C.R.B. and V.M.W.). This work was also supported by a grant from the Korea Health Technology R&D project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C3418). The biospecimens for multiplex immunohistochemistry were provided by Samsung Medical Center BioBank.

Publisher Copyright:
© 2018, The Author(s).

ASJC Scopus subject areas

Cell Biology

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10.1038/s41556-018-0183-3

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Barnes, J. M., Kaushik, S., Bainer, R. O., Sa, J. K., Woods, E. C., Kai, F. B., Przybyla, L., Lee, M., Lee, H. W., Tung, J. C., Maller, O., Barrett, A. S., Lu, K. V., Lakins, J. N., Hansen, K. C., Obernier, K., Alvarez-Buylla, A., Bergers, G., Phillips, J. J., ... Weaver, V. M. (2018). A tension-mediated glycocalyx–integrin feedback loop promotes mesenchymal-like glioblastoma. Nature Cell Biology, 20(10), 1203-1214. https://doi.org/10.1038/s41556-018-0183-3

Barnes, JM, Kaushik, S, Bainer, RO, Sa, JK, Woods, EC, Kai, FB, Przybyla, L, Lee, M, Lee, HW, Tung, JC, Maller, O, Barrett, AS, Lu, KV, Lakins, JN, Hansen, KC, Obernier, K, Alvarez-Buylla, A, Bergers, G, Phillips, JJ, Nam, DH, Bertozzi, CR & Weaver, VM 2018, 'A tension-mediated glycocalyx–integrin feedback loop promotes mesenchymal-like glioblastoma', Nature Cell Biology, vol. 20, no. 10, pp. 1203-1214. https://doi.org/10.1038/s41556-018-0183-3

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title = "A tension-mediated glycocalyx–integrin feedback loop promotes mesenchymal-like glioblastoma",

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.",

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

note = "Funding Information: We thank W. Weiss (UCSF) for the S100β-vErb:p53+/– mice and M. Paszek (Cornell University) for helpful discussions. Animal handling and tissue preparation was supported by L. Korets and N. Korets (UCSF). This work was supported by the following grants: US National Institutes of Health NCI R01 grants CA138818-01A1, CA192914-01, CA174929-01 and CA085482 (V.M.W.); U01 grant CA202241 (V.M.W. and F.K.); U54 grant CA163155 (V.M.W.); Ruth Kirschstein NRSA F32 CA174319 (J.M.B.); UCSF Brain Tumor Research Program T32 CA151022 (J.M.B.); NHLBI T32 HL007544 (J.C.T.); UCSF Brain Tumor SPORE Tissue Core NIH/NCI P50 CA097257 (J.J.P.); NIH 1U01CA168878 (J.J.P); NIH/NINDS R01 NS081117 (J.J.P.); CIRM grant RB5-07409 (V.M.W.); CIRM training grant TG2-01153 (L.P.); and NCI R01 CA227942 (C.R.B. and V.M.W.). This work was also supported by a grant from the Korea Health Technology R&D project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C3418). The biospecimens for multiplex immunohistochemistry were provided by Samsung Medical Center BioBank. Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = oct,

day = "1",

doi = "10.1038/s41556-018-0183-3",

language = "English",

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T1 - A tension-mediated glycocalyx–integrin feedback loop promotes mesenchymal-like glioblastoma

AU - Barnes, J. Matthew

AU - Kaushik, Shelly

AU - Bainer, Russell O.

AU - Sa, Jason K.

AU - Woods, Elliot C.

AU - Kai, Fui Boon

AU - Przybyla, Laralynne

AU - Lee, Mijeong

AU - Lee, Hye Won

AU - Tung, Jason C.

AU - Maller, Ori

AU - Barrett, Alexander S.

AU - Lu, Kan V.

AU - Lakins, Jonathon N.

AU - Hansen, Kirk C.

AU - Obernier, Kirsten

AU - Alvarez-Buylla, Arturo

AU - Bergers, Gabriele

AU - Phillips, Joanna J.

AU - Nam, Do Hyun

AU - Bertozzi, Carolyn R.

AU - Weaver, Valerie M.

N1 - Funding Information: We thank W. Weiss (UCSF) for the S100β-vErb:p53+/– mice and M. Paszek (Cornell University) for helpful discussions. Animal handling and tissue preparation was supported by L. Korets and N. Korets (UCSF). This work was supported by the following grants: US National Institutes of Health NCI R01 grants CA138818-01A1, CA192914-01, CA174929-01 and CA085482 (V.M.W.); U01 grant CA202241 (V.M.W. and F.K.); U54 grant CA163155 (V.M.W.); Ruth Kirschstein NRSA F32 CA174319 (J.M.B.); UCSF Brain Tumor Research Program T32 CA151022 (J.M.B.); NHLBI T32 HL007544 (J.C.T.); UCSF Brain Tumor SPORE Tissue Core NIH/NCI P50 CA097257 (J.J.P.); NIH 1U01CA168878 (J.J.P); NIH/NINDS R01 NS081117 (J.J.P.); CIRM grant RB5-07409 (V.M.W.); CIRM training grant TG2-01153 (L.P.); and NCI R01 CA227942 (C.R.B. and V.M.W.). This work was also supported by a grant from the Korea Health Technology R&D project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C3418). The biospecimens for multiplex immunohistochemistry were provided by Samsung Medical Center BioBank. Publisher Copyright: © 2018, The Author(s).

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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.

AB - 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.

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

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