title: Epigenetic states of cells of origin and tumor evolution drive tumor-initiating cell phenotype and tumor heterogeneity.
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.
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Kin-Hoe
authors.initials: KH
authors.lastname: Chow
authors.affiliation: Laboratory of Immunogenetics, NIAID/NIH, Bethesda, Maryland. Department of Food and Nutrition, Seoul National University, Seoul, Korea.
authors.forename: Dong-Mi
authors.initials: DM
authors.lastname: Shin
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Molly H
authors.initials: MH
authors.lastname: Jenkins
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Miller
authors.affiliation: Division of Neurosurgery, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Canada.
authors.forename: David J
authors.initials: DJ
authors.lastname: Shih
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Seungbum
authors.initials: S
authors.lastname: Choi
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Low
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Vivek
authors.initials: V
authors.lastname: Philip
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Brad
authors.initials: B
authors.lastname: Rybinski
authors.affiliation: Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.affiliation: Division of Neurosurgery, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine. Kyuson.yun@jax.org.
authors.forename: Kyuson
authors.initials: K
authors.lastname: Yun
mesh_terms: D000818:Animals; D044127:Epigenesis, Genetic / Q000235:genetics*; D053823:Hedgehog Proteins / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000235:genetics; D008527:Medulloblastoma / Q000235:genetics / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000473:pathology*; D058953:Neural Stem Cells / Q000473:pathology; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D051057:Proto-Oncogene Proteins c-akt