Epigenetic states of cells of origin and tumor evolution drive tumor-initiating cell phenotype and tumor heterogeneity

Kin-Hoe Chow, Dong-Mi Shin, Molly H Jenkins, Emily E Miller, David J Shih, Seungbum Choi, Benjamin E Low, Vivek Philip, Brad Rybinski, Roderick T Bronson, Michael D Taylor, Kyuson Yun

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

A central confounding factor in the development of targeted therapies is tumor cell heterogeneity, particularly in tumor-initiating cells (TIC), within clinically identical tumors. Here, we show how activation of the Sonic Hedgehog (SHH) pathway in neural stem and progenitor cells creates a foundation for tumor cell evolution to heterogeneous states that are histologically indistinguishable but molecularly distinct. In spontaneous medulloblastomas that arise in Patched (Ptch)(+/-) mice, we identified three distinct tumor subtypes. Through cell type-specific activation of the SHH pathway in vivo, we determined that different cells of origin evolved in unique ways to generate these subtypes. Moreover, TICs in each subtype had distinct molecular and cellular phenotypes. At the bulk tumor level, the three tumor subtypes could be distinguished by a 465-gene signature and by differential activation levels of the ERK and AKT pathways. Notably, TICs from different subtypes were differentially sensitive to SHH or AKT pathway inhibitors, highlighting new mechanisms of resistance to targeted therapies. In summary, our results show how evolutionary processes act on distinct cells of origin to contribute to tumoral heterogeneity, at both bulk tumor and TIC levels.

Original languageEnglish (US)
Pages (from-to)4864-74
Number of pages11
JournalCancer research
Volume74
Issue number17
DOIs
StatePublished - Sep 1 2014

Keywords

  • Animals
  • Epigenesis, Genetic
  • Hedgehog Proteins
  • MAP Kinase Signaling System
  • Medulloblastoma
  • Mice
  • Neoplastic Stem Cells
  • Neural Stem Cells
  • Phenotype
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction
  • Journal Article
  • Research Support, N.I.H., Extramural

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