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 to 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. Pharmacological 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.

中文翻译：

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弥漫性脑桥神经胶质瘤 (DIPG) 的转录组学分析确定了高致瘤性癌症干细胞样细胞的可靶向 ALDH 阳性亚群

迫切需要了解弥漫性脑桥脑胶质瘤 (DIPG) 中的癌症干细胞 (CSC) 格局，以解决治疗耐药性并确定新的治疗方法。患者来源的 DIPG 细胞通过流式细胞术证明了醛脱氢酶 (ALDH) 和 CD133 的异质表达。转录组水平表征确定了 ALDH+ 中 MYC、E2F、DNA 损伤修复 (DDR) 基因、糖酵解代谢和 mTOR 信号传导的升高的 mRNA 水平，而 ALDH- 则支持茎样表型并指示可药用靶标。ALDH+ 细胞表现出增殖增加、神经球形成和引发肿瘤，导致原位植入时存活率降低。药理学 MAPK/PI3K/mTOR 靶向下调 MYC、E2F 和 DDR mRNA 并减少糖酵解代谢。体内 PI3K/mTOR 靶向可能通过降低癌症干性来抑制侧腹和 ALDH+ 原位肿瘤模型中的肿瘤生长。总之，我们描述了由于代谢增加而具有增殖特性的 ALDH+ DIPG 的存在，这可能受微环境的调节，并可能导致耐药性和肿瘤复发。启示：ALDH+ DIPG 的表征与靶向 MAPK/PI3K/mTOR 信号传导相结合，为旨在解决 DIPG 中 CSC 表型的分子靶向治疗提供了动力。这可能受到微环境的调节，并可能导致耐药性和肿瘤复发。启示：ALDH+ DIPGs 的表征与靶向 MAPK/PI3K/mTOR 信号传导相结合，为旨在解决 DIPG 中 CSC 表型的分子靶向治疗提供了动力。这可能受到微环境的调节，并可能导致耐药性和肿瘤复发。启示：ALDH+ DIPGs 的表征与靶向 MAPK/PI3K/mTOR 信号传导相结合，为旨在解决 DIPG 中 CSC 表型的分子靶向治疗提供了动力。