Dataset Information

A multi-omics analysis of glioma chemoresistance using a hybrid microphysiological model of glioblastoma

ABSTRACT: Chemoresistance is a major clinical challenge in management of glioblastoma (GBM) Temozolomide (TMZ) is the chemotherapeutic drug of choice for GBM; however, the therapeutic effect of TMZ is limited due to the development of resistance. Recapitulating GBM chemoresistance in a controlled environment is thus essential in understanding the mechanism of chemoresistance. Herein, we present a hybrid microphysiological model of chemoresistant GBM-on-a-chip (HGoC) by directly co-culturing TMZ-resistant GBM spheroids with healthy neurons to mimic the microenvironment of both the tumor and the surrounding healthy tissue. We characterized the model with proteomics, lipidomics, and secretome assays. The results showed that our artificial model recapitulated the molecular signatures of recurrent GBM in humans. Both showed alterations in vesicular transport and cholesterol pathways, mitotic quiescence, and a switch in metabolism to oxidative phosphorylation associated with a transition from mesenchymal to amoeboid. This is the first report to unravel the interplay of all these molecular changes as a mechanism of chemoresistance in glioblastoma. Moreover, we have shown that acquisition of resistance increases invasiveness and the presence of neurons decreases this property. 1. Seyfoori, A., et al., Self-filling microwell arrays (SFMAs) for tumor spheroid formation. Lab Chip, 2018. 18(22): p. 3516-3528. 2. Amereh, M., et al., In-Silico Modeling of Tumor Spheroid Formation and Growth. Micromachines (Basel), 2021. 12(7). 3. Senko, M.W., et al., Novel Parallelized Quadrupole/Linear Ion Trap/Orbitrap Tribrid Mass Spectrometer Improving Proteome Coverage and Peptide Identification Rates. Analytical Chemistry, 2013. 85(24): p. 11710-11714. 4. Zhou, G., et al., NetworkAnalyst 3.0: a visual analytics platform for comprehensive gene expression profiling and meta-analysis. Nucleic Acids Res, 2019. 47(W1): p. W234-w241. 5. Xia, J., E.E. Gill, and R.E. Hancock, NetworkAnalyst for statistical, visual and network-based meta-analysis of gene expression data. Nat Protoc, 2015. 10(6): p. 823-44. 6. Breuer, K., et al., InnateDB: systems biology of innate immunity and beyond--recent updates and continuing curation. Nucleic Acids Res, 2013. 41(Database issue): p. D1228-33.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Glioblastoma

SUBMITTER: Rui Vitorino

LAB HEAD: Mohsen Akbari

PROVIDER: PXD037753 | Pride | 2025-06-09

REPOSITORIES: Pride

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Publications

Tumoroid Model Reveals Synergistic Impairment of Metabolism by Iron Chelators and Temozolomide in Chemo-Resistant Patient-derived Glioblastoma Cells.

Amereh Meitham M Seyfoori Amir A Shojaei Shahla S Lane Sarah S Zhao Tian T Shokrollahi Barough Mahdieh M Lum Julian J JJ Walter Patrick P Akbari Mohsen M

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20250426 20

Chemoresistance poses a significant clinical challenge in managing glioblastoma (GBM), limiting the long-term success of traditional treatments. Here, a 3D tumoroid model is used to investigate the metabolic sensitivity of temozolomide (TMZ)-resistant GBM cells to iron chelation by deferoxamine (DFO) and deferiprone (DFP). This work shows that TMZ-resistant GBM cells acquire stem-like characteristics, higher intracellular iron levels, higher expression of aconitase, and elevated reliance on oxid ...[more]

PMID: 40285641

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Project description:Glioblastoma (GBM) carries a dismal prognosis largely due to acquired resistance to the standard treatment, which incorporates the chemotherapy temozolomide (TMZ). Inhibiting the proteasomal pathway is an emerging strategy, where combination treatments are under clinical investigation. We hypothesized that pre-treatment of GBM with bortezomib (BTZ) might sensitize glioblastoma to TMZ by abolishing autophagy survival signals to augment DNA damage and apoptosis. P3 patient-derived GBM cells as well as the tumor cell lines U87, HF66, A172 and T98G were investigated for clonogenic survival after single or combined treatment with TMZ and BTZ in vitro. Change in autophagic flux was examined after experimental treatments in conjunction with inhibitors of autophagy or downregulation of autophagy-related genes -5 and -7 (ATG5 and ATG7, respectively). Autophagic flux was increased in TMZ-resistant P3 and T98G cells as indicated by diminished levels of the autophagy markers LC3A/B-II and increased STX17, higher protein degradation and no formation of p62 bodies nor induction of apoptosis. In contrast, BTZ treatment attenuated ULK1 mRNA, total and phosphorylated protein, and accumulated LC3A/B-II, p62 and autophagosomes analogously to Baf1 and chloroquine autophagy inhibitors. These autophagosomes did not fuse with lysosomes, indicated by attenuated STX17 expression and reduced degradation of long-lived proteins, which culminated in enhanced caspase-3/8 dependent apoptosis. BTZ synergistically enhanced TMZ efficacy, attenuated tumor cell proliferation, triggered ATM/Chk2 DNA damage signalling to further augment caspase-3/8 mediated apoptosis in the TMZ resistant P3 and T98G GBM cells. Genetic or chemical inhibition of autophagy (with CRISPR-CAs9 ATG5, ATG7 shRNA, MRT68921 or VPS34-IN1) abrogated BTZ efficacy and rescued BTZ+ TMZ treated GBM cells from death. We conclude that Bortezomib ameliorates temozolomide resistance through ATG5/7-dependent abrogated autophagic flux and may be amenable in combination treatment regimens for TMZ refractory GBM patients.

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