2. Academic Validation
  3. 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

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. 2023 Aug 30;e2302280. doi: 10.1002/smll.202302280.
Maxine Sy Lam 1 2,  Joey Jy Aw 1,  Damien Tan 1,  Ragavi Vijayakumar 1,  Hui Yi Grace Lim 1,  Swathi Yada 1,  Qing You Pang 3,  Nick Barker 1,  Carol Tang 3 4 5,  Beng Ti Ang 4 6,  Radoslaw M Sobota 1 2,  Andrea Pavesi 1 7
Affiliations

Affiliations

  • 1 Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Singapore, 138673, Singapore.
  • 2 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.
  • 3 Neuro-Oncology Research Laboratory, Department of Research, National Neuroscience Institute, Singapore, 308433, Singapore.
  • 4 Duke-National University of Singapore Medical School, Singapore, 169857, Singapore.
  • 5 School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore.
  • 6 Department of Neurosurgery, National Neuroscience Institute, Singapore, 308433, Singapore.
  • 7 Mechanobiology Institute, National University of Singapore, Singapore, 117411, Singapore.
PMID: 37649234 DOI: 10.1002/smll.202302280
Abstract

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.

Keywords

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

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