PT  - JOURNAL ARTICLE
AU  - Surowiec, Rachel K.
AU  - Ferris, Sarah F.
AU  - Apfelbaum, April
AU  - Espinoza, Carlos
AU  - Mehta, Ranjit K.
AU  - Monchamp, Karamoja
AU  - Sirihorachai, Veerin R.
AU  - Bedi, Karan
AU  - Ljungman, Mats
AU  - Galban, Stefanie
TI  - Transcriptomic Analysis of Diffuse Intrinsic Pontine Glioma (DIPG) Identifies a Targetable ALDH-Positive Subset of Highly Tumorigenic Cancer Stem-like Cells
AID  - 10.1158/1541-7786.MCR-20-0464
DP  - 2020 Oct 26
TA  - Molecular Cancer Research
4099  - http://mcr.aacrjournals.org/content/early/2020/11/12/1541-7786.MCR-20-0464.short
4100  - http://mcr.aacrjournals.org/content/early/2020/11/12/1541-7786.MCR-20-0464.full
AB  - 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. ALDH+ 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 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.