Abstract
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. Tumors shape a microenvironmental network by acting as a source of tumor-associated astrocytes that provide paracrine stimulation to microglia to secret IGF1, which is critical for tumor progression in SHH-activated mouse medulloblastoma models.
Original language | English (US) |
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Pages (from-to) | 502-520.e19 |
Journal | Cell |
Volume | 180 |
Issue number | 3 |
DOIs | |
State | Published - Feb 6 2020 |
Keywords
- TME
- astrocytes
- brain tumor
- cellular network
- medulloblastoma
- microglia
- paracrine signaling
- trans-differentiation
- tumor microenvironment
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology