ArticleCancer research2014
Epigenetic states of cells of origin and tumor evolution drive tumor-initiating cell phenotype and tumor heterogeneity.
Article in Cancer research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 24 citations in OpenAlex.
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- Intratumoral heterogeneity and drug resistance in cancer.Cancer cell international · 2025Review
- Cancer stem cells, not bulk tumor cells, determine mechanisms of resistance to SMO inhibitors.Cancer research communications · 2022Article
- Promotion of gastric tumor initiating cells in a 3D collagen gel culture model via YBX1/SPP1/NF-κB signaling.Cancer cell international · 2021Article
- Cryptic developmental events determine medulloblastoma radiosensitivity and cellular heterogeneity without altering transcriptomic profile.Communications biology · 2021Article
- Antiapoptotic Bcl-2 family proteins BCL-xL and MCL-1 integrate neural progenitor survival and proliferation during postnatal cerebellar neurogenesis.Cell death and differentiation · 2021Article
- HDAC and MAPK/ERK Inhibitors Cooperate To Reduce Viability and Stemness in Medulloblastoma.Journal of molecular neuroscience : MN · 2020Article
- Tumor heterogeneity of gastric cancer: From the perspective of tumor-initiating cell.World journal of gastroenterology · 2018Review
- A unified model of the hierarchical and stochastic theories of gastric cancer.British journal of cancer · 2017Review
- Genome-wide methylation analysis identifies a core set of hypermethylated genes in CIMP-H colorectal cancer.BMC cancer · 2017Article
- Cancer metastasis: enactment of the script for human reproductive drama.Cancer cell international · 2017Article
- Addressing intra-tumoral heterogeneity and therapy resistance.Oncotarget · 2016Review
- Radiation Sensitivity in a Preclinical Mouse Model of Medulloblastoma Relies on the Function of the Intrinsic Apoptotic Pathway.Cancer research · 2016Article
- Characterization of novel biomarkers in selecting for subtype specific medulloblastoma phenotypes.Oncotarget · 2015Article
- Epigenetic mechanisms in cancer: push and pull between kneaded erasers and fate writers.International journal of nanomedicine · 2015Review
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
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.
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Registered trials
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