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

Abstract

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.

Rapid PTEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy

“…These stem-like cells are responsible for tumor initiation and have been linked to therapy resistance and cancer regrowth after treatment 51-53 . Aldehyde dehydrogenase (ALDH) has been proposed as a BTIC marker in both pediatric and adult gliomas 54,55 . We quantified ALDH expression after AZD4573, IR, or combination and observed a significant depletion of the ALDH+ cell fraction following combinatorial therapy ( Figure 5c and Extended Data Figure 6 ).…”

“…These stem-like cells are responsible for tumor initiation and have been linked to therapy resistance and cancer regrowth after treatment [51][52][53] . Aldehyde dehydrogenase (ALDH) has been proposed as a BTIC marker in both pediatric and adult gliomas 54,55 .…”

A DNA Repair and Cell Cycle Gene Expression Signature in Pediatric High-Grade Gliomas: Prognostic and Therapeutic Value

“…Finally, other determinants may underlie the segregation seen with our cohorts. Indeed, alterations in DNA repair gene expression have recently been associated to glycolytic metabolism and mTor signaling, which is frequently upregulated in all pHGGs [ 39 ].…”

Advanced Spheroid, Tumouroid and 3D Bioprinted In-Vitro Models of Adult and Paediatric Glioblastoma

“…The population of radially migrating cells at the periphery of HGGs commonly host CSCS-also termed glioma stem cells (GSCS) and glioma initiating cells (GICS) [31][32][33][34][35]that can self-renew [36], are drug resistant and radioresistant [27,32,34,37] and indicate poor prognosis [11,38]. Studies suggest that CSCS are also present in DMG [35]. They are thought to be a key contributor to high recurrence rates and therapy resistance [30,36,39].…”