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Published Online: 16 March 2021

Matrix Stiffness Modulates Patient-Derived Glioblastoma Cell Fates in Three-Dimensional Hydrogels

Publication: Tissue Engineering Part A
Volume 27, Issue Number 5-6

Abstract

Cancer progression is known to be accompanied by changes in tissue stiffness. Previous studies have primarily employed immortalized cell lines and 2D hydrogel substrates, which do not recapitulate the 3D tumor niche. How matrix stiffness affects patient-derived cancer cell fate in 3D remains unclear. In this study, we report a matrix metalloproteinase-degradable poly(ethylene-glycol)-based hydrogel platform with brain-mimicking biochemical cues and tunable stiffness (40–26,600 Pa) for 3D culture of patient-derived glioblastoma xenograft (PDTX GBM) cells. Our results demonstrate that decreasing hydrogel stiffness enhanced PDTX GBM cell proliferation, and hydrogels with stiffness 240 Pa and below supported robust PDTX GBM cell spreading in 3D. PDTX GBM cells encapsulated in hydrogels demonstrated higher drug resistance than 2D control, and increasing hydrogel stiffness further enhanced drug resistance. Such 3D hydrogel platforms may provide a valuable tool for mechanistic studies of the role of niche cues in modulating cancer progression for different cancer types.

Abstract

Impact statement

Cancer progression has been demonstrated to be accompanied by changes in tissue stiffness; however, how matrix stiffness affects patient-derived glioblastoma xenograft glioblastoma (PDTX GBM) cells in 3D remains elusive. By employing a biomimetic hydrogel platform with brain-mimicking biochemical cues and tunable stiffness (40–26,600 Pa), we demonstrated the effect of varying hydrogel stiffness on PDTX GBM cell proliferation, spreading, and drug resistance in 3D, which cannot be recapitulated using 2D culture. Such 3D hydrogel platforms may provide a valuable tool for mechanistic studies or drug discovery and screening using patient-derived GBM cells.

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Information & Authors

Information

Published In

cover image Tissue Engineering Part A
Tissue Engineering Part A
Volume 27Issue Number 5-6March 2021
Pages: 390 - 401
PubMed: 32731804

History

Published online: 16 March 2021
Published in print: March 2021
Published ahead of print: 6 November 2020
Published ahead of production: 31 July 2020
Accepted: 17 July 2020
Received: 29 April 2020

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Affiliations

Christine Wang
Department of Bioengineering, Schools of Engineering and Medicine, Stanford University, Stanford, California, USA.
Sauradeep Sinha
Department of Bioengineering, Schools of Engineering and Medicine, Stanford University, Stanford, California, USA.
Xinyi Jiang
Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA.
Luke Murphy
Department of Bioengineering, Schools of Engineering and Medicine, Stanford University, Stanford, California, USA.
Sergio Fitch
Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA.
Christy Wilson
Department of Neurosurgery, Stanford University, School of Medicine, Stanford, California, USA.
Gerald Grant
Department of Neurosurgery, Stanford University, School of Medicine, Stanford, California, USA.
Department of Bioengineering, Schools of Engineering and Medicine, Stanford University, Stanford, California, USA.
Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA.

Notes

Address correspondence to: Fan Yang, PhD, Department of Bioengineering, Schools of Engineering and Medicine, Stanford University, 300 Pasteur Dr., Edwards R105, Stanford, CA 94305, USA [email protected]

Disclosure Statement

No competing financial interests exist.

Funding Information

This work was supported by the following grants: NIH R01DE024772 (F.Y.), NIH 1R01AR074502 (F.Y.), the Stanford Child Health Research Institute Faculty Scholar Award (F.Y.), Stanford Bio-X IIP grant award (F. Y.), and the Alliance for Cancer Gene Therapy Young Investigator award grant (F.Y.).

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