Title: Astrocytic trans-Differentiation Completes a Multicellular Paracrine Feedback Loop Required for Medulloblastoma Tumor Growth
Author: Maojin Yao, P. Britten Ventura, Ying Jiang, Fausto J. Rodriguez, Lixin Wang, Justin S.A. Perry, Yibo Yang, Kelsey Wahl, Rowena B. Crittenden, Mariko L. Bennett, Lin Qi, Cong-Cong Gong, Xiao-Nan Li, Ben A. Barres, Timothy P. Bender, Kodi S. Ravichandran, Kevin A. Janes, Charles G. Eberhart, Hui Zong
Issue&Volume: January 23, 2020
Abstract: The tumor microenvironment (TME) is critical for tumor progression. However, the establishmentand function of the TME remain obscure because of its complex cellular composition.Using a mouse genetic system called mosaic analysis with double markers (MADMs), wedelineated TME evolution at single-cell resolution in sonic hedgehog (SHH)-activatedmedulloblastomas 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 neverdifferentiate into astrocytes. Second, we identified that TME-derived IGF1 promotestumor progression. Third, we uncovered that insulin-like growth factor 1 (IGF1) isproduced by tumor-associated microglia in response to interleukin-4 (IL-4) stimulation.Finally, we found that IL-4 is secreted by TuAstrocytes. Collectively, our studiesreveal an evolutionary process that produces a multi-lateral network within the TMEof medulloblastoma: a fraction of tumor cells trans-differentiate into TuAstrocytes, which, in turn, produce IL-4 that stimulates microgliato produce IGF1 to promote tumor progression.