Subclonal evolution and expansion of spatially distinct THY1-positive cells is associated with recurrence in glioblastoma

Glioblastoma(GBM) is a lethal disease characterized by inevitable recurrence. Here we investigate the molecular pathways mediating resistance, with the goal of identifying novel therapeutic opportunities. We developed a longitudinal in vivo recurrence model utilizing patient-derived explants to prod...

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Published in:Neoplasia (New York, N.Y.) N.Y.), 2023-02, Vol.36, p.100872, Article 100872
Main Authors: Al-Holou, Wajd N., Wang, Hanxiao, Ravikumar, Visweswaran, Shankar, Sunita, Oneka, Morgan, Fehmi, Ziad, Verhaak, Roel GW, Kim, Hoon, Pratt, Drew, Camelo-Piragua, Sandra, Speers, Corey, Wahl, Daniel R, Hollon, Todd, Sagher, Oren, Heth, Jason A, Muraszko, Karin M., Lawrence, Theodore S., de Carvalho, Ana C, Mikkelsen, Tom, Rao, Arvind, Rehemtulla, Alnawaz
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents, Alkylating - pharmacology
Brain Neoplasms - pathology
Cell Line, Tumor
Drug Resistance, Neoplasm - genetics
Glioblastoma
Glioblastoma - metabolism
Humans
Mice
Neoplasm Recurrence, Local - drug therapy
Neoplasm Recurrence, Local - genetics
Original Research
Subclonal evolution
Temozolomide - pharmacology
Treatment resistance
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Summary:Glioblastoma(GBM) is a lethal disease characterized by inevitable recurrence. Here we investigate the molecular pathways mediating resistance, with the goal of identifying novel therapeutic opportunities. We developed a longitudinal in vivo recurrence model utilizing patient-derived explants to produce paired specimens(pre- and post-recurrence) following temozolomide(TMZ) and radiation(IR). These specimens were evaluated for treatment response and to identify gene expression pathways driving treatment resistance. Findings were clinically validated using spatial transcriptomics of human GBMs. These studies reveal in replicate cohorts, a gene expression profile characterized by upregulation of mesenchymal and stem-like genes at recurrence. Analyses of clinical databases revealed significant association of this transcriptional profile with worse overall survival and upregulation at recurrence. Notably, gene expression analyses identified upregulation of TGFβ signaling, and more than one-hundred-fold increase in THY1 levels at recurrence. Furthermore, THY1-positive cells represented
ISSN:1476-5586
1522-8002
1476-5586
DOI:10.1016/j.neo.2022.100872