Recommended Citation
Al-Holou WN, Wang H, Ravikumar V, Shankar S, Oneka M, Fehmi Z, Verhaak RG, Kim H, Pratt D, Camelo-Piragua S, Speers C, Wahl DR, Hollon T, Sagher O, Heth JA, Muraszko KM, Lawrence TS, de Carvalho AC, Mikkelsen T, Rao A, and Rehemtulla A. Subclonal evolution and expansion of spatially distinct THY1-positive cells is associated with recurrence in glioblastoma. Neoplasia 2023; 36:100872.
Document Type
Article
Publication Date
2-1-2023
Publication Title
Neoplasia (New York, N.Y.)
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 <10% of cells in treatment-naïve tumors, compared to 75-96% in recurrent tumors. We then isolated THY1-positive cells from treatment-naïve patient samples and determined that they were inherently resistant to chemoradiation in orthotopic models. Additionally, using image-guided biopsies from treatment-naïve human GBM, we conducted spatial transcriptomic analyses. This revealed rare THY1+ regions characterized by mesenchymal/stem-like gene expression, analogous to our recurrent mouse model, which co-localized with macrophages within the perivascular niche. We then inhibited TGFBRI activity in vivo which decreased mesenchymal/stem-like protein levels, including THY1, and restored sensitivity to TMZ/IR in recurrent tumors.
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.
Medical Subject Headings
Animals; Mice; Humans; Glioblastoma; Cell Line, Tumor; Brain Neoplasms; Neoplasm Recurrence, Local; Temozolomide; Drug Resistance, Neoplasm; Antineoplastic Agents, Alkylating
PubMed ID
36621024
Volume
36
First Page
100872
Last Page
100872
