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

• 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
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-20-0464

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.