Transcriptomic analysis of diffuse intrinsic pontine glioma (DIPG) identifies a targetable ALDH-positive subset of highly tumorigenic cancer stem-like cells

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Abstract

Understanding the cancer stem cell (CSC) landscape in diffuse intrinsic pontine glioma (DIPG) is desperately needed to address treatment resistance and identify novel therapeutic approaches. Patient-derived DIPG cells demonstrated heterogeneous expression of aldehyde dehydrogenase (ALDH) and CD133 by flow cytometry. Transcriptome-level characterization identified elevated mRNA levels of MYC, E2F, DNA damage repair (DDR) genes, glycolytic metabolism, and mTOR signaling in ALDH+ compared with ALDH-, supporting a stem-like phenotype and indicating a druggable target. ALDHþ cells demonstrated increased proliferation, neurosphere formation, and initiated tumors that resulted in decreased survival when orthotopically implanted. Pharmacologic MAPK/PI3K/mTOR targeting downregulated MYC, E2F, and DDR mRNAs and reduced glycolytic metabolism. In vivo PI3K/mTOR targeting inhibited tumor growth in both flank and an ALDHþ orthotopic tumor model likely by reducing cancer stemness. In summary, we describe existence of ALDH+ DIPGs with proliferative properties due to increased metabolism, which may be regulated by the microenvironment and likely contributing to drug resistance and tumor recurrence. Implications: Characterization of ALDHþ DIPGs coupled with targeting MAPK/PI3K/mTOR signaling provides an impetus for molecularly targeted therapy aimed at addressing the CSC phenotype in DIPG.

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Surowiec, R. K., Ferris, S. F., Apfelbaum, A., Espinoza, C., Mehta, R. K., Monchamp, K., … Galban, S. (2021). Transcriptomic analysis of diffuse intrinsic pontine glioma (DIPG) identifies a targetable ALDH-positive subset of highly tumorigenic cancer stem-like cells. Molecular Cancer Research, 19(2), 223–239. https://doi.org/10.1158/1541-7786.MCR-20-0464

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