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

Cell. 2020 Feb 6;180(3):502-520.e19. doi: 10.1016/j.cell.2019.12.024. Epub 2020 Jan 23.

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.

Keywords: TME; astrocytes; brain tumor; cellular network; medulloblastoma; microglia; paracrine signaling; trans-differentiation; tumor microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Astrocytes / metabolism*
  • Carcinogenesis / metabolism*
  • Cell Lineage
  • Cell Transdifferentiation*
  • Cerebellar Neoplasms / metabolism*
  • Cerebellar Neoplasms / pathology
  • Disease Models, Animal
  • Female
  • Hedgehog Proteins / metabolism
  • Heterografts
  • Humans
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism
  • Interleukin-4 / genetics
  • Interleukin-4 / metabolism
  • Male
  • Medulloblastoma / metabolism*
  • Medulloblastoma / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / metabolism
  • Paracrine Communication*
  • Tumor Microenvironment

Substances

  • Hedgehog Proteins
  • IGF1 protein, human
  • Il4 protein, mouse
  • SHH protein, human
  • insulin-like growth factor-1, mouse
  • Interleukin-4
  • Insulin-Like Growth Factor I