Document Type
Article
Publication Date
2-1-2023
Original Citation
Al-Holou W,
Wang H,
Ravikumar V,
Shankar S,
Oneka M,
Fehmi Z,
Verhaak RG,
Kim H,
Pratt D,
Camelo-Piragua S,
Speers C,
Wahl D,
Hollon T,
Sagher O,
Heth J,
Muraszko K,
Lawrence T,
de Carvalho A,
Mikkelsen T,
Rao A,
Rehemtulla A.
Subclonal evolution and expansion of spatially distinct THY1-positive cells is associated with recurrence in glioblastoma. Neoplasia. 2023;36:100872.
Keywords
JGM, Animals, Mice, Humans, Glioblastoma, Cell Line, Tumor, Brain Neoplasms, Neoplasm Recurrence, Local, Temozolomide, Drug Resistance, Neoplasm, Antineoplastic Agents, Alkylating
JAX Source
Neoplasia. 2023;36:100872.
ISSN
1476-5586
PMID
36621024
DOI
https://doi.org/10.1016/j.neo.2022.100872
Grant
Research reported in this publication was supported by National In- stitute of Health(NIH) grants P01-CA085878 and 5R01CA241764. Re- search was supported by the National Cancer Institute (NCI) of the NIH under award number P30CA046592. M.O. V.R., and A. Rao were sup- ported by National Cancer Institute (NCI) R37CA214955, a gift from Agilent Technologies, a University of Michigan MIDAS PODS Grant, and a Research Scholar Grant from the American Cancer Society (RSG-16- 005-01). Research was also supported by the Department of Defense (CA180174), the NIH/Michigan Institute for Clinical and Health Re- search (UL1TR002240), the Congress of Neurological Surgeons Tumor fellowship, the American Brain Tumor Association, and the Christina Costa Brain Tumor Research Fund.
Abstract
PURPOSE: 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.
EXPERIMENTAL DESIGN: 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.
RESULTS: 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
CONCLUSIONS: These findings reveal that GBM recurrence may result from tumor repopulation by pre-existing, therapy-resistant, THY1-positive, mesenchymal cells within the perivascular niche.
Comments
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)