title: High-fat diet enhances stemness and tumorigenicity of intestinal progenitors.
abstract: Little is known about how pro-obesity diets regulate tissue stem and progenitor cell function. Here we show that high-fat diet (HFD)-induced obesity augments the numbers and function of Lgr5(+) intestinal stem cells of the mammalian intestine. Mechanistically, a HFD induces a robust peroxisome proliferator-activated receptor delta (PPAR-δ) signature in intestinal stem cells and progenitor cells (non-intestinal stem cells), and pharmacological activation of PPAR-δ recapitulates the effects of a HFD on these cells. Like a HFD, ex vivo treatment of intestinal organoid cultures with fatty acid constituents of the HFD enhances the self-renewal potential of these organoid bodies in a PPAR-δ-dependent manner. Notably, HFD- and agonist-activated PPAR-δ signalling endow organoid-initiating capacity to progenitors, and enforced PPAR-δ signalling permits these progenitors to form in vivo tumours after loss of the tumour suppressor Apc. These findings highlight how diet-modulated PPAR-δ activation alters not only the function of intestinal stem and progenitor cells, but also their capacity to initiate tumours.
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, Massachusetts 02139, USA.|Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Semir
authors.initials: S
authors.lastname: Beyaz
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, Massachusetts 02139, USA.
authors.forename: Miyeko D
authors.initials: MD
authors.lastname: Mana
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, Massachusetts 02139, USA.|Division of Gastroenterology and Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111, USA.
authors.forename: Jatin
authors.initials: J
authors.lastname: Roper
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, Massachusetts 02139, USA.|Departments of Pathology, Gastroenterology, and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Kedrin
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Assieh
authors.initials: A
authors.lastname: Saadatpour
authors.affiliation: Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Sue-Jean
authors.initials: SJ
authors.lastname: Hong
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, Massachusetts 02139, USA.
authors.forename: Khristian E
authors.initials: KE
authors.lastname: Bauer-Rowe
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, Massachusetts 02139, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Xifaras
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, Massachusetts 02139, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Akkad
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, Massachusetts 02139, USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Arias
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Pinello
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Yarden
authors.initials: Y
authors.lastname: Katz
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, Massachusetts 02139, USA.
authors.forename: Shweta
authors.initials: S
authors.lastname: Shinagare
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, Massachusetts 02139, USA.|Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Monther
authors.initials: M
authors.lastname: Abu-Remaileh
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, Massachusetts 02139, USA.|Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Mihaylova
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.
authors.forename: Dudley W
authors.initials: DW
authors.lastname: Lamming
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, Massachusetts 02139, USA.
authors.forename: Rizkullah
authors.initials: R
authors.lastname: Dogum
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Guoji
authors.initials: G
authors.lastname: Guo
authors.affiliation: Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: George W
authors.initials: GW
authors.lastname: Bell
authors.affiliation: Departments of Pathology, Gastroenterology, and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Selig
authors.affiliation: Departments of Pathology, Gastroenterology, and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: G Petur
authors.initials: GP
authors.lastname: Nielsen
authors.affiliation: Division of Digestive Diseases, University of Mississippi Medical Center, Jackson, Missisippi 39216, USA.
authors.forename: Nitin
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Departments of Pathology, Gastroenterology, and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Ferrone
authors.affiliation: Departments of Pathology, Gastroenterology, and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Vikram
authors.initials: V
authors.lastname: Deshpande
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Guo-Cheng
authors.initials: GC
authors.lastname: Yuan
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, Massachusetts 02139, USA.|Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, Massachusetts 02142, USA.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, Massachusetts 02139, USA.|Departments of Pathology, Gastroenterology, and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Ömer H
authors.initials: ÖH
authors.lastname: Yilmaz
mesh_terms: D000818:Animals; D002452:Cell Count; D000066673:Cell Self Renewal / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000473:pathology*; D059305:Diet, High-Fat / Q000009:adverse effects*; D005260:Female; D017491:Genes, APC; D006801:Humans; D007422:Intestines / Q000473:pathology*; D008297:Male; D051379:Mice; D009765:Obesity / Q000139:chemically induced / Q000473:pathology; D009940:Organoids / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047494:PPAR delta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D055153:Stem Cell Niche / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D047494:PPAR delta; D051176:beta Catenin