2. Academic Validation
  3. Single-Nucleus RNA-Sequencing Reveals a MET+ Oligodendrocyte Subpopulation That Promotes Proliferation of Radiation-Induced Gliomas

Single-Nucleus RNA-Sequencing Reveals a MET+ Oligodendrocyte Subpopulation That Promotes Proliferation of Radiation-Induced Gliomas

  • Int J Radiat Oncol Biol Phys. 2024 Sep 12:S0360-3016(24)03330-3. doi: 10.1016/j.ijrobp.2024.09.007.
Meng Huang 1,  Xinmiao Long 2,  Shao Xu 3,  Xiudan Zhan 3,  Gu Gong 4,  Wei Gao 2,  Mingrui Li 4,  Meng Yao 3,  Qing Liu 4,  Minghua Wu 2,  Wei Zhao 5,  Wenyong Long 6
Affiliations

Affiliations

  • 1 Department of Neurosurgery in Xiangya Hospital, Central South University, Changsha, China; Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China; Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
  • 2 Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China; FuRong Laboratory, Changsha, China.
  • 3 Key Laboratory of Stem Cells and Tissue Engineering, Sun Yat-Sen University, Ministry of Education, Guangzhou, China.
  • 4 Department of Neurosurgery in Xiangya Hospital, Central South University, Changsha, China.
  • 5 Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China; Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
  • 6 Department of Neurosurgery in Xiangya Hospital, Central South University, Changsha, China. Electronic address: wylongdr@csu.edu.cn.
PMID: 39265740 DOI: 10.1016/j.ijrobp.2024.09.007
Abstract

Purpose: Radiation-induced gliomas (RIGs) are fatal late complications of radiation therapy, with a median survival time of 6 to 11 months. RIGs demonstrate a unique molecular landscape and may originate from a glial lineage distinct from that of primary malignancies or diffuse midline gliomas (DMGs). This study aimed to explore the intratumoral diversity within RIGs to uncover their cellular origin and characteristics and enhance our understanding of this uncommon tumor type.

Methods and materials: Formalin-fixed, paraffin-embedded samples were collected from 2 RIGs and 2 DMGs for single-nucleus RNA Sequencing. A detailed analysis was conducted to assess intratumoral heterogeneity and cellular interactions, including gene set enrichment, pseudotime trajectory, and cell communication analyses. Immunofluorescence staining, proliferation assay, and RNA-seq analysis were also applied to validate our findings.

Results: Our analysis revealed distinct heterogeneity in oligodendrocytes (ODs) between the DMG and RIG samples. A unique subpopulation of ODs in RIGs, which was characterized by gene encoding mesenchymal-epithelial transition factor (MET), and therefore termed MET+ ODs, exhibited characteristics typical of Cancer cells, such as increased mitotic activity, cancer-related gene expression, and extensive copy number variations. Cell communication studies indicated that MET+ ODs interact vigorously with G1/S and G2/M cycling cells via the neural cell adhesion molecule signaling pathway, potentially enhancing the proliferation of cycling malignant cells. Integrating our results with existing RNA-seq data further supported our hypothesis. The presence of MET+ ODs in RIGs was confirmed by immunostaining, and activation of the neural cell adhesion molecule signaling pathway in vitro significantly promoted the proliferation of RIG tumor cells. Moreover, in vitro radiation induced the transformation of ODs to be more similar to MET+ ODs.

Conclusions: RIGs are characterized by an OD composition distinct from that of DMGs. A specific subpopulation of MET+ ODs in RIGs may be crucial in tumorigenesis and promote the growth of malignant cells. Identifying MET+ ODs offers a valuable target for future clinical surveillance and therapeutic strategies.

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