期刊
CELL
卷 180, 期 3, 页码 502-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2019.12.024
关键词
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资金
- NIH/NINDS pre-doctoral fellowship [F31-NS076313]
- Mark Foundation fellowship from the Cancer Research Institute
- NCI [1K99CA237728-01]
- Burroughs Wellcome PDEP award
- Pew Charitable Trusts
- [DoD W81XWH-11-1-0557]
- [NIH R01NS097271]
- [R01CA194470]
- [U01CA215794]
- [R21HL143025]
- [R01NS055089]
The tumor microenvironment (TME) is critical for tumor progression. However, the establishment and function of the TME remain obscure because of its complex cellular composition. Using a mouse genetic system called mosaic analysis with double markers (MADMs), we delineated TME evolution at single-cell resolution in sonic hedgehog (SHH)-activated medulloblastomas that originate from unipotent granule neuron progenitors in the brain. First, we found that astrocytes within the TME(TuAstrocytes) were trans-differentiated from tumor granule neuron precursors (GNPs), which normally never differentiate into astrocytes. Second, we identified that TME-derived IGF1 promotes tumor progression. Third, we uncovered that insulin-like growth factor 1 (IGF1) is produced by tumor-associated microglia in response to interleukin-4 (IL-4) stimulation. Finally, we found that IL-4 is secreted by TuAstrocytes. Collectively, our studies reveal an evolutionary process that produces a multi-lateral network within the TME of medulloblastoma: a fraction of tumor cells trans-differentiate into TuAstrocytes, which, in turn, produce IL-4 that stimulates microglia to produce IGF1 to promote tumor progression.
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