Multiplexed single-cell lineage tracing of mitotic kinesin inhibitor resistance in glioblastoma.

Autor:	Cheng YL; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, 10032, USA., Banu MA; Department of Neurological Surgery, Columbia University Irving Medical Center, New York, NY, 10032, USA., Zhao W; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, 10032, USA., Rosenfeld SS; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA., Canoll P; Department of Pathology & Cell Biology, Columbia University Irving Medical Center, New York, NY, 10032, USA., Sims PA; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, 10032, USA.; Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, NY, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Sep 12. Date of Electronic Publication: 2023 Sep 12.
DOI:	10.1101/2023.09.09.557001
Abstrakt:	Glioblastoma (GBM) is a deadly brain tumor, and the kinesin motor KIF11 is an attractive therapeutic target because of its dual roles in proliferation and invasion. The clinical utility of KIF11 inhibitors has been limited by drug resistance, which has mainly been studied in animal models. We used multiplexed lineage tracing barcodes and scRNA-seq to analyze drug resistance time courses for patient-derived GBM neurospheres treated with ispinesib, a potent KIF11 inhibitor. Similar to GBM progression in patients, untreated cells lost their neural lineage identity and transitioned to a mesenchymal phenotype, which is associated with poor prognosis. In contrast, cells subjected to long-term ispinesib treatment exhibited a proneural phenotype. We generated patient-derived xenografts to show that ispinesib-resistant cells form less aggressive tumors in vivo , even in the absence of drug. Finally, we used lineage barcodes to nominate drug combination targets by retrospective analysis of ispinesib-resistant clones in the drug-naïve setting and identified drugs that are synergistic with ispinesib. Competing Interests: COMPETING INTERESTS P.A.S. is listed as an inventor on patent applications and issued patents filed by Columbia University related to the microwell technology described here. P.A.S. receives patent royalties from Guardant Health. The remaining authors declare that they have no competing interests.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu