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 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 MAPKJPI3K/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 sternness. 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.

Automated summary

ALDH(+) DIPG cells exhibit stem-like properties with increased proliferation and neurosphere formation, as well as higher metabolic activity. Pharmacologic targeting of MAPKJPI3K/mTOR can reduce the stem-like characteristics of DIPGs, inhibiting tumor growth.