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
  • 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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