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

• Published in: Cell Vol. 180; no. 3; pp. 502 - 520.e19
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.02.2020
• Subjects: Animals; astrocytes; Astrocytes - metabolism; brain; brain tumor; Carcinogenesis - metabolism; Cell Lineage; Cell Transdifferentiation; cellular network; Cerebellar Neoplasms - metabolism; Cerebellar Neoplasms - pathology; Disease Models, Animal; Female; Hedgehog Proteins - metabolism; Heterografts; Humans; insulin-like growth factor I; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; interleukin-4; Interleukin-4 - genetics; Interleukin-4 - metabolism; Male; medulloblastoma; Medulloblastoma - metabolism; Medulloblastoma - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; microglia; neoplasm cells; neoplasm progression; neoplasms; neurons; Neurons - metabolism; Paracrine Communication; paracrine signaling; TME; trans-differentiation; Tumor Microenvironment; paracrine signaling; medulloblastoma; trans-differentiation; cellular network; brain tumor; tumor microenvironment; astrocytes; TME; microglia
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2019.12.024

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. [Display omitted] •A small number of medulloblastoma cells trans-differentiated into TME astrocytes•Astrocytes in human SHH-subtype medulloblastoma share lineage with tumor cells•Tumor-derived astrocytes secret IL-4 to polarize microglia for IGF1 production•IGF1 from tumor associated microglia is critical for 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.