Exploring Responses of Glioblastoma Patient-Derived Cell Cultures to Drugs Reveals New Therapeutic Opportunities

Iwona Anna Ciechomska; Kamil Wojnicki; Bartosz Wojtas; Paulina Szadkowska; Katarzyna Poleszak; Beata Kaza; Kinga Jaskula; Wiktoria Dawidczyk; Ryszard Czepko; Mariusz Banach; Bartosz Czapski; Pawel Nauman; Katarzyna Kotulska; Wiesława Grajkowska; Marcin Roszkowski; Tomasz Czernicki; Andrzej Marchel; Bozena Kaminska

doi:10.20944/preprints202301.0585.v1

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preprints.org > life sciences > molecular biology > doi: 10.20944/preprints202301.0585.v1

Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Exploring Responses of Glioblastoma Patient-Derived Cell Cultures to Drugs Reveals New Therapeutic Opportunities

Iwona Anna Ciechomska

^* ,

Version 1 : Received: 30 January 2023 / Approved: 31 January 2023 / Online: 31 January 2023 (12:01:04 CET)

A peer-reviewed article of this Preprint also exists.

Ciechomska, I.A.; Wojnicki, K.; Wojtas, B.; Szadkowska, P.; Poleszak, K.; Kaza, B.; Jaskula, K.; Dawidczyk, W.; Czepko, R.; Banach, M.; Czapski, B.; Nauman, P.; Kotulska, K.; Grajkowska, W.; Roszkowski, M.; Czernicki, T.; Marchel, A.; Kaminska, B. Exploring Novel Therapeutic Opportunities for Glioblastoma Using Patient-Derived Cell Cultures. Cancers 2023, 15, 1562. Ciechomska, I.A.; Wojnicki, K.; Wojtas, B.; Szadkowska, P.; Poleszak, K.; Kaza, B.; Jaskula, K.; Dawidczyk, W.; Czepko, R.; Banach, M.; Czapski, B.; Nauman, P.; Kotulska, K.; Grajkowska, W.; Roszkowski, M.; Czernicki, T.; Marchel, A.; Kaminska, B. Exploring Novel Therapeutic Opportunities for Glioblastoma Using Patient-Derived Cell Cultures. Cancers 2023, 15, 1562.

DOI: 10.3390/cancers15051562

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Abstract

Glioblastomas (GBM) are most common, primary brain tumors in adults. Despite advances in neurosurgery, radio- and chemotherapy, the median survival of GBM patients is 15 months. Recent large-scale genomic, transcriptomic and epigenetic analyses have shown the cellular and molecular heterogeneity of GBMs, which hampers the outcomes of standard therapies. We have established 13 GBM-derived cell cultures from fresh tumor specimens and characterized them molecularly using RNAseq, immunoblotting and immunocytochemistry. Evaluation of proneural (OLIG2, IDH1R132H, TP53 and PDGFRα), classical (EGFR) and mesenchymal markers (CHI3L1/YKL40, CD44 and phospho-STAT3), as well as expression of pluripotency (SOX2, OLIG2, NESTIN) and differentiation (GFAP, MAP2, β-Tubulin III) markers revealed the striking inter-tumor heterogeneity of primary GBM cell cultures. Upregulated expression of VIMENTIN, N-CADHERIN and CD44 at mRNA/protein levels suggested increased epithelial to mesenchymal transition (EMT) in most studied cell cultures. The effects of temozolomide (TMZ) or doxorubicin (DOX) were tested in three GBM-derived cell cultures with different methylation status of the MGMT promoter. Amongst TMZ- or DOX-treated cultures the strongest accumulation of apoptotic markers: caspase 7 and PARP were found in WG4 cells with methylated MGMT suggesting that its methylation status predicts vulnerability to both drugs. As many GBM-derived cells showed high EGFR levels, we tested the effects of AG1478, an EGFR inhibitor, on downstream signaling pathways. AG1478 caused decreased levels of phospho-STAT3, thus inhibition of active STAT3 augmented antitumor effects of DOX and TMZ in cells with methylated and intermediate status of MGMT. Altogether, our findings show that GBM-derived cell cultures mimic the considerable tumor heterogeneity and identifying patient-specific signaling vulnerabilities can assist in overcoming therapy resistance, by providing personalized combinatorial treatment recommendations.

Keywords

glioblastoma; cancer stem cells; EMT; MGMT; temozolomide; doxorubicin; STAT3; EGFR inhibitor (AG1478)

Subject

LIFE SCIENCES, Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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