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

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

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)502-520.e19
JournalCell
Volume180
Issue number3
DOIs
StatePublished - Feb 6 2020

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Keywords

  • TME
  • astrocytes
  • brain tumor
  • cellular network
  • medulloblastoma
  • microglia
  • paracrine signaling
  • trans-differentiation
  • tumor microenvironment

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Yao, M., Ventura, P. B., Jiang, Y., Rodriguez, F. J., Wang, L., Perry, J. S. A., Yang, Y., Wahl, K., Crittenden, R. B., Bennett, M. L., Qi, L., Gong, C. C., Li, X. N., Barres, B. A., Bender, T. P., Ravichandran, K. S., Janes, K. A., Eberhart, C. G., & Zong, H. (2020). Astrocytic trans-Differentiation Completes a Multicellular Paracrine Feedback Loop Required for Medulloblastoma Tumor Growth. Cell, 180(3), 502-520.e19. https://doi.org/10.1016/j.cell.2019.12.024