2. Academic Validation
  3. FXR Regulates Intestinal Cancer Stem Cell Proliferation

FXR Regulates Intestinal Cancer Stem Cell Proliferation

  • Cell. 2019 Feb 21;176(5):1098-1112.e18. doi: 10.1016/j.cell.2019.01.036.
Ting Fu 1,  Sally Coulter 2,  Eiji Yoshihara 1,  Tae Gyu Oh 1,  Sungsoon Fang 3,  Fritz Cayabyab 1,  Qiyun Zhu 4,  Tong Zhang 5,  Mathias Leblanc 1,  Sihao Liu 1,  Mingxiao He 1,  Wanda Waizenegger 1,  Emanuel Gasser 1,  Bernd Schnabl 6,  Annette R Atkins 1,  Ruth T Yu 1,  Rob Knight 7,  Christopher Liddle 2,  Michael Downes 8,  Ronald M Evans 9
Affiliations

Affiliations

  • 1 Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • 2 Storr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Westmead NSW 2145, Australia.
  • 3 Severance Biomedical Science Institute, BK21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, South Korea.
  • 4 Department of Medicine, University of California San Diego, La Jolla, CA 92037, USA.
  • 5 Waitt Biophotonics Core, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • 6 Department of Pediatrics, University of California San Diego, La Jolla, CA 92037, USA.
  • 7 Department of Medicine, University of California San Diego, La Jolla, CA 92037, USA; Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA 92037, USA.
  • 8 Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: [email protected].
  • 9 Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: [email protected].
PMID: 30794774 DOI: 10.1016/j.cell.2019.01.036
Abstract

Increased levels of intestinal bile acids (BAs) are a risk factor for colorectal Cancer (CRC). Here, we show that the convergence of dietary factors (high-fat diet) and dysregulated Wnt signaling (APC mutation) alters BA profiles to drive malignant transformations in Lgr5-expressing (Lgr5+) Cancer Stem Cells and promote an adenoma-to-adenocarcinoma progression. Mechanistically, we show that BAs that antagonize intestinal farnesoid X receptor (FXR) function, including tauro-β-muricholic acid (T-βMCA) and deoxycholic acid (DCA), induce proliferation and DNA damage in Lgr5+ cells. Conversely, selective activation of intestinal FXR can restrict abnormal Lgr5+ cell growth and curtail CRC progression. This unexpected role for FXR in coordinating intestinal self-renewal with BA levels implicates FXR as a potential therapeutic target for CRC.

Keywords

BA-FXR axis; Lgr5(+) intestinal stem cells; colon cancer progression; genetic and dietary risk factors.

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