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.

blood-brain barrier chemoresistance dia-PASEF glioblastoma microfluidic models spatial heterogeneity

Journal

Small (Weinheim an der Bergstrasse, Germany)
ISSN: 1613-6829
Titre abrégé: Small
Pays: Germany
ID NLM: 101235338

Informations de publication

Date de publication:
30 Aug 2023
Historique:
revised: 26 06 2023
received: 17 03 2023
medline: 31 8 2023
pubmed: 31 8 2023
entrez: 31 8 2023
Statut: aheadofprint

Résumé

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.

Identifiants

pubmed: 37649234
doi: 10.1002/smll.202302280
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

e2302280

Subventions

Organisme : A*STAR Career Development Fund
ID : C210112058
Organisme : Singapore Ministry of Health's National Medical Research Council
Organisme : Clinician Scientist - Individual Research
ID : NMRC/CIRG/1441/2016
Organisme : Open Fund-Large Collaborative
ID : MOH-000541-00
Organisme : A.P., N.B. and R.M.S. are supported by A*STAR Core funding

Informations de copyright

© 2023 The Authors. Small published by Wiley-VCH GmbH.

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Auteurs

Maxine Sy Lam (MS)

Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Singapore, 138673, Singapore.
Functional Proteomics Laboratory, SingMass National Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Singapore, 138673, Singapore.

Joey Jy Aw (JJ)

Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Singapore, 138673, Singapore.

Damien Tan (D)

Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Singapore, 138673, Singapore.

Ragavi Vijayakumar (R)

Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Singapore, 138673, Singapore.

Hui Yi Grace Lim (HYG)

Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Singapore, 138673, Singapore.

Swathi Yada (S)

Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Singapore, 138673, Singapore.

Qing You Pang (QY)

Neuro-Oncology Research Laboratory, Department of Research, National Neuroscience Institute, Singapore, 308433, Singapore.

Nick Barker (N)

Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Singapore, 138673, Singapore.

Carol Tang (C)

Neuro-Oncology Research Laboratory, Department of Research, National Neuroscience Institute, Singapore, 308433, Singapore.
Duke-National University of Singapore Medical School, Singapore, 169857, Singapore.
School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore.

Beng Ti Ang (BT)

Duke-National University of Singapore Medical School, Singapore, 169857, Singapore.
Department of Neurosurgery, National Neuroscience Institute, Singapore, 308433, Singapore.

Radoslaw M Sobota (RM)

Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Singapore, 138673, Singapore.
Functional Proteomics Laboratory, SingMass National Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Singapore, 138673, Singapore.

Andrea Pavesi (A)

Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Singapore, 138673, Singapore.
Mechanobiology Institute, National University of Singapore, Singapore, 117411, Singapore.

Classifications MeSH