Unveiling the influence of tumor microenvironment and spatial heterogeneity on temozolomide resistance in glioblastoma using an advanced human in vitro model of the blood-brain barrier and glioblastoma

Glioblastoma (GBM) is the most common primary malignant brain cancer in adults with a dismal prognosis. Temozolomide (TMZ) is the first-in-line chemotherapeutic; however, resistance is frequent and multifactorial. While many molecular and genetic factors have been linked to TMZ resistance, the role...

Full description

Saved in:
Bibliographic Details
Main Authors: Lam, Maxine S. Y., Aw, Joey J. Y., Tan, Damien, Vijayakumar, Ragavi, Lim, Grace Hui Yi, Yada, Swathi, Pang, Qing You, Barker, Nick, Tang, Carol, Ang, Beng Ti, Sobota, Radoslaw M., Pavesi, Andrea
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2024
Subjects:
Online Access:https://hdl.handle.net/10356/174305
Tags: Add Tag
No Tags, Be the first to tag this record!
Institution: Nanyang Technological University
Language: English
id sg-ntu-dr.10356-174305
record_format dspace
spelling sg-ntu-dr.10356-1743052024-04-01T15:32:05Z Unveiling the influence of tumor microenvironment and spatial heterogeneity on temozolomide resistance in glioblastoma using an advanced human in vitro model of the blood-brain barrier and glioblastoma Lam, Maxine S. Y. Aw, Joey J. Y. Tan, Damien Vijayakumar, Ragavi Lim, Grace Hui Yi Yada, Swathi Pang, Qing You Barker, Nick Tang, Carol Ang, Beng Ti Sobota, Radoslaw M. Pavesi, Andrea School of Biological Sciences National Neuroscience Institute Duke-National University of Singapore Medical School Medicine, Health and Life Sciences Blood-brain barrier Chemoresistance Glioblastoma (GBM) is the most common primary malignant brain cancer in adults with a dismal prognosis. Temozolomide (TMZ) is the first-in-line chemotherapeutic; however, resistance is frequent and multifactorial. While many molecular and genetic factors have been linked to TMZ resistance, the role of the solid tumor morphology and the tumor microenvironment, particularly the blood-brain barrier (BBB), is unknown. Here, the authors investigate these using a complex in vitro model for GBM and its surrounding BBB. The model recapitulates important clinical features such as a dense tumor core with tumor cells that invade along the perivascular space; and a perfusable BBB with a physiological permeability and morphology that is altered in the presence of a tumor spheroid. It is demonstrated that TMZ sensitivity decreases with increasing cancer cell spatial organization, and that the BBB can contribute to TMZ resistance. Proteomic analysis with next-generation low volume sample workflows of these cultured microtissues revealed potential clinically relevant proteins involved in tumor aggressiveness and TMZ resistance, demonstrating the utility of complex in vitro models for interrogating the tumor microenvironment and therapy validation. Published version This research was supported by A*STAR Career Development Fund (C210112058) awarded to M.S.Y.L. R.M.S., and A.P. are supported by A*STAR core funding. In this study, de-identified GBM cells were established from patients with informed consent, from the National Neuroscience Institute, Singapore. This resource is supported by the Singapore Ministry of Health's National Medical Research Council under its Translational and Clinical Research Flagship Programme-Tier 1 (Project No: NMRC/ TCR/016-NNI/2016) awarded to B.T. Ang, and the Open Fund-Large Collaborative Grant (OF-LCG) Tier 1 (MOH-000541-00) awarded to B.T. Ang as program lead. 2024-03-26T01:13:42Z 2024-03-26T01:13:42Z 2023 Journal Article Lam, M. S. Y., Aw, J. J. Y., Tan, D., Vijayakumar, R., Lim, G. H. Y., Yada, S., Pang, Q. Y., Barker, N., Tang, C., Ang, B. T., Sobota, R. M. & Pavesi, A. (2023). Unveiling the influence of tumor microenvironment and spatial heterogeneity on temozolomide resistance in glioblastoma using an advanced human in vitro model of the blood-brain barrier and glioblastoma. Small, 19(52), e2302280-. https://dx.doi.org/10.1002/smll.202302280 1613-6810 https://hdl.handle.net/10356/174305 10.1002/smll.202302280 37649234 2-s2.0-85169314562 52 19 e2302280 en Small © 2023 The Authors. Small published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Medicine, Health and Life Sciences
Blood-brain barrier
Chemoresistance
spellingShingle Medicine, Health and Life Sciences
Blood-brain barrier
Chemoresistance
Lam, Maxine S. Y.
Aw, Joey J. Y.
Tan, Damien
Vijayakumar, Ragavi
Lim, Grace Hui Yi
Yada, Swathi
Pang, Qing You
Barker, Nick
Tang, Carol
Ang, Beng Ti
Sobota, Radoslaw M.
Pavesi, Andrea
Unveiling the influence of tumor microenvironment and spatial heterogeneity on temozolomide resistance in glioblastoma using an advanced human in vitro model of the blood-brain barrier and glioblastoma
description Glioblastoma (GBM) is the most common primary malignant brain cancer in adults with a dismal prognosis. Temozolomide (TMZ) is the first-in-line chemotherapeutic; however, resistance is frequent and multifactorial. While many molecular and genetic factors have been linked to TMZ resistance, the role of the solid tumor morphology and the tumor microenvironment, particularly the blood-brain barrier (BBB), is unknown. Here, the authors investigate these using a complex in vitro model for GBM and its surrounding BBB. The model recapitulates important clinical features such as a dense tumor core with tumor cells that invade along the perivascular space; and a perfusable BBB with a physiological permeability and morphology that is altered in the presence of a tumor spheroid. It is demonstrated that TMZ sensitivity decreases with increasing cancer cell spatial organization, and that the BBB can contribute to TMZ resistance. Proteomic analysis with next-generation low volume sample workflows of these cultured microtissues revealed potential clinically relevant proteins involved in tumor aggressiveness and TMZ resistance, demonstrating the utility of complex in vitro models for interrogating the tumor microenvironment and therapy validation.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Lam, Maxine S. Y.
Aw, Joey J. Y.
Tan, Damien
Vijayakumar, Ragavi
Lim, Grace Hui Yi
Yada, Swathi
Pang, Qing You
Barker, Nick
Tang, Carol
Ang, Beng Ti
Sobota, Radoslaw M.
Pavesi, Andrea
format Article
author Lam, Maxine S. Y.
Aw, Joey J. Y.
Tan, Damien
Vijayakumar, Ragavi
Lim, Grace Hui Yi
Yada, Swathi
Pang, Qing You
Barker, Nick
Tang, Carol
Ang, Beng Ti
Sobota, Radoslaw M.
Pavesi, Andrea
author_sort Lam, Maxine S. Y.
title Unveiling the influence of tumor microenvironment and spatial heterogeneity on temozolomide resistance in glioblastoma using an advanced human in vitro model of the blood-brain barrier and glioblastoma
title_short Unveiling the influence of tumor microenvironment and spatial heterogeneity on temozolomide resistance in glioblastoma using an advanced human in vitro model of the blood-brain barrier and glioblastoma
title_full Unveiling the influence of tumor microenvironment and spatial heterogeneity on temozolomide resistance in glioblastoma using an advanced human in vitro model of the blood-brain barrier and glioblastoma
title_fullStr Unveiling the influence of tumor microenvironment and spatial heterogeneity on temozolomide resistance in glioblastoma using an advanced human in vitro model of the blood-brain barrier and glioblastoma
title_full_unstemmed Unveiling the influence of tumor microenvironment and spatial heterogeneity on temozolomide resistance in glioblastoma using an advanced human in vitro model of the blood-brain barrier and glioblastoma
title_sort unveiling the influence of tumor microenvironment and spatial heterogeneity on temozolomide resistance in glioblastoma using an advanced human in vitro model of the blood-brain barrier and glioblastoma
publishDate 2024
url https://hdl.handle.net/10356/174305
_version_ 1795375048299642880