Transcriptomic Analysis of Diffuse Intrinsic Pontine Glioma (DIPG) Identifies a Targetable ALDH-Positive Subset of Highly Tumorigenic Cancer Stem-like Cells

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 b...

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Bibliographic Details
Published in:Molecular cancer research 2021-02, Vol.19 (2), p.223-239
Main Authors: Surowiec, Rachel K, Ferris, Sarah F, Apfelbaum, April, Espinoza, Carlos, Mehta, Ranjit K, Monchamp, Karamoja, Sirihorachai, Veerin R, Bedi, Karan, Ljungman, Mats, Galban, Stefanie
Format: Article
Language:English
Subjects:
Aldehyde Dehydrogenase - metabolism
Animals
Cell Line, Tumor
Diffuse Intrinsic Pontine Glioma - genetics
Diffuse Intrinsic Pontine Glioma - pathology
Humans
Male
Mice
Neoplastic Stem Cells - metabolism
Transcriptome - genetics
Xenograft Model Antitumor Assays
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Summary: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 , 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. ALDH cells demonstrated increased proliferation, neurosphere formation, and initiated tumors that resulted in decreased survival when orthotopically implanted. Pharmacologic MAPK/PI3K/mTOR targeting downregulated , and mRNAs and reduced glycolytic metabolism. PI3K/mTOR targeting inhibited tumor growth in both flank and an ALDH 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 ALDH DIPGs coupled with targeting MAPK/PI3K/mTOR signaling provides an impetus for molecularly targeted therapy aimed at addressing the CSC phenotype in DIPG.
ISSN:1541-7786
1557-3125
DOI:10.1158/1541-7786.MCR-20-0464