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Guo D , Wang Y , Cheng Y , Liao S , Hu J , Du F , Xu G , Liu Y , Cai KQ , Cheung M , Wainwright BJ , Lu QR , Zhao Y , Yang ZJ
Tumor cells generate astrocyte-like cells that contribute to SHH-driven medulloblastoma relapse
J Exp Med. 2021 Sep 6;218(9)
PMID: 34254999    PMCID: PMC8282281   
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Abstract
Astrocytes, a major glial cell type in the brain, play a critical role in supporting the progression of medulloblastoma (MB), the most common malignant pediatric brain tumor. Through lineage tracing analyses and single-cell RNA sequencing, we demonstrate that astrocytes are predominantly derived from the transdifferentiation of tumor cells in relapsed MB (but not in primary MB), although MB cells are generally believed to be neuronal-lineage committed. Such transdifferentiation of MB cells relies on Sox9, a transcription factor critical for gliogenesis. Our studies further reveal that bone morphogenetic proteins (BMPs) stimulate the transdifferentiation of MB cells by inducing the phosphorylation of Sox9. Pharmacological inhibition of BMP signaling represses MB cell transdifferentiation into astrocytes and suppresses tumor relapse. Our studies establish the distinct cellular sources of astrocytes in primary and relapsed MB and provide an avenue to prevent and treat MB relapse by targeting tumor cell transdifferentiation.
Notes
1540-9538 Guo, Duancheng Orcid: 0000-0002-5915-7390 Wang, Yuan Orcid: 0000-0002-5084-0804 Cheng, Yan Orcid: 0000-0002-9604-3771 Liao, Shengyou Orcid: 0000-0001-6999-9551 Hu, Jian Orcid: 0000-0002-4449-7333 Du, Fang Orcid: 0000-0002-1277-6290 Xu, Gang Orcid: 0000-0001-9203-4803 Liu, Yongqiang Orcid: 0000-0003-3826-6878 Cai, Kathy Q Orcid: 0000-0002-6034-3377 Cheung, Martin Orcid: 0000-0002-3471-8534 Wainwright, Brandon J Orcid: 0000-0003-0406-2092 Lu, Q Richard Orcid: 0000-0001-6846-9014 Zhao, Yi Orcid: 0000-0001-6046-8420 Yang, Zeng-Jie Orcid: 0000-0003-1205-0964 RSG1605301NEC/American Cancer Society/ DG1900025/American Brain Tumor Association/ CURE 4100068716/Pennsylvania CURE Health Research Fund/ Journal Article J Exp Med. 2021 Sep 6;218(9):e20202350. doi: 10.1084/jem.20202350. Epub 2021 Jul 13.