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Cheng Y , Franco-Barraza J , Wang Y , Zheng C , Zhang L , Qu Y , Long Y , Cukierman E , Yang ZJ
Sustained hedgehog signaling in medulloblastoma tumoroids is attributed to stromal astrocytes and astrocyte-derived extracellular matrix
Lab Invest. 2020 Sep;100(9) :1208-1222
PMID: 32457352    PMCID: PMC7442735    URL: https://www.ncbi.nlm.nih.gov/pubmed/32457352
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Abstract
Aberrant activation of the hedgehog (Hh) signaling pathway is associated with the formation of medulloblastoma (MB), the most common malignant pediatric brain tumor. However, tumor cells from human and mouse MB can not be passaged or preserved after being adherently cultured. Moreover, Hh signaling in MB cells is inactivated in such culture. Here we demonstrate that MB cells are capable of forming tumoroids (tumor spheroids) in vitro under optimized conditions, which can be further passaged and cryopreserved. More importantly, MB cells maintain Hh pathway activation and cell proliferation in tumoroids. Our studies further reveal that tumoroids-forming capacity of MB cells relies on astrocytes, a major component of the MB microenvironment. Astrocytes facilitate the formation of MB tumoroids by secreting sonic hedgehog (Shh) and generating astrocyte-derived extracellular matrix. These findings demonstrate the critical role of stromal astrocytes in supporting the survival and proliferation of MB cells in vitro. This study establishes a valid model for long-term culture of primary MB cells, which could be greatly beneficial for future investigation of MB tumorigenicity and the development of improved approaches to treat MB.
Notes
1530-0307 Cheng, Yan Franco-Barraza, Janusz ORCID: http://orcid.org/0000-0003-3652-5311 Wang, Yuan Zheng, Chaonan Zhang, Li Qu, Yanghui Long, Yaqiu Cukierman, Edna ORCID: http://orcid.org/0000-0002-1452-9576 Yang, Zeng-Jie R01 CA232256/CA/NCI NIH HHS/United States R21 CA231252/CA/NCI NIH HHS/United States Journal Article United States Lab Invest. 2020 May 26. pii: 10.1038/s41374-020-0443-2. doi: 10.1038/s41374-020-0443-2.