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

Abstract

<div>Abstract<p>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 <i>MYC, E2F</i>, DNA damage repair (DDR) genes, glycolytic metabolism, and mTOR signaling in ALDH<sup>+</sup> compared with ALDH<sup>−</sup>, supporting a stem-like phenotype and indicating a druggable target. ALDH<sup>+</sup> cells demonstrated increased proliferation, neurosphere formation, and initiated tumors that resulted in decreased survival when orthotopically implanted. Pharmacologic MAPK/PI3K/mTOR targeting downregulated <i>MYC, E2F</i>, and <i>DDR</i> mRNAs and reduced glycolytic metabolism. <i>In vivo</i> PI3K/mTOR targeting inhibited tumor growth in both flank and an ALDH<sup>+</sup> orthotopic tumor model likely by reducing cancer stemness. In summary, we describe existence of ALDH<sup>+</sup> DIPGs with proliferative properties due to increased metabolism, which may be regulated by the microenvironment and likely contributing to drug resistance and tumor recurrence.</p>Implications:<p>Characterization of ALDH<sup>+</sup> DIPGs coupled with targeting MAPK/PI3K/mTOR signaling provides an impetus for molecularly targeted therapy aimed at addressing the CSC phenotype in DIPG.</p></div>