期刊
MOLECULAR CANCER RESEARCH
卷 19, 期 2, 页码 223-239出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-20-0464
关键词
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资金
- ChadTough/Michael Mosier Defeat DIPG foundation
- MD Anderson Cancer Center support Grant [5 P30 CA016672-40]
- Bru-Sequencing [1 R01 CA213214, UM1 HG009382]
- NCI of the NIH [P30CA046592, P30 CA04659229]
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.
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.
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