Astrocytic trans-Differentiation Completes a Multicellular Paracrine Feedback Loop Required for Medulloblastoma Tumor Growth

作者：Yao, Maojin; Ventura, P. Britten; Jiang, Ying; Rodriguez, Fausto J.; Wang, Lixin; Perry, Justin S. A.; Yang, Yibo; Wahl, Kelsey; Crittenden, Rowena B.; Bennett, Mariko L.; Qi, Lin; Gong, Cong-Cong; Li, Xiao-Nan; Barres, Ben A.; Bender, Timothy P.; Ravichandran, Kodi S.; Janes, Kevin A.; Eberhart, Charles G.; Zong, Hui^*

来源：Cell, 2020, 180(3): 502-+.

DOI：10.1016/j.cell.2019.12.024

• CARCINOMA-ASSOCIATED FIBROBLASTS
• CANCER-ASSOCIATED FIBROBLASTS
• MOSAIC ANALYSIS
• DOUBLE MARKERS
• MACROPHAGE RECRUITMENT
• CD11B EXPRESSION
• MOUSE MODELS
• TNF-ALPHA
• IN-VIVO
• T-CELLS

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.

• 单位
  西北大学