title: In vivo epigenetic reprogramming of primary human colon cancer cells enhances metastases.
abstract: How metastases develop is not well understood and no genetic mutations have been reported as specific metastatic drivers. Here we have addressed the idea that epigenetic reprogramming by GLI-regulated pluripotent stemness factors promotes metastases. Using primary human colon cancer cells engrafted in mice, we find that transient expression of OCT4, SOX2, KLF4 +/- cMYC establishes an enhanced pro-metastatic state in the primary tumor that is stable through sequential engraftments and is transmitted through clonogenic cancer stem cells. Metastatic reprogramming alters NANOG methylation and stably boosts NANOG and NANOGP8 expression. Metastases and reprogrammed EMT-like phenotypes require endogenous NANOG, but enhanced NANOG is not sufficient to induce these phenotypes. Finally, reprogrammed tumors enhance GLI2, and we show that GLI2(high) and AXIN2(low), which are markers of the metastatic transition of colon cancers, are prognostic of poor disease outcome in patients. We propose that metastases arise through epigenetic reprogramming of cancer stem cells within primary tumors.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, CH-1211 Geneva, Switzerland.
authors.forename: Grigori
authors.initials: G
authors.lastname: Singovski
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, CH-1211 Geneva, Switzerland.
authors.forename: Carolina
authors.initials: C
authors.lastname: Bernal
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, CH-1211 Geneva, Switzerland.
authors.forename: Monika
authors.initials: M
authors.lastname: Kuciak
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, CH-1211 Geneva, Switzerland.
authors.forename: Irene
authors.initials: I
authors.lastname: Siegl-Cachedenier
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, CH-1211 Geneva, Switzerland.
authors.forename: Arwen
authors.initials: A
authors.lastname: Conod
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, CH-1211 Geneva, Switzerland Ariel.RuizAltaba@unige.ch.
authors.forename: Ariel
authors.initials: A
authors.lastname: Ruiz i Altaba
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D065150:Cellular Reprogramming / Q000235:genetics*; D002999:Clone Cells; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000090062:Kruppel-Like Factor 4; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D014157:Transcription Factors
keywords: GLI; NANOG; cancer stem cells; epigenetic reprogramming; metastases