FXR Regulates Intestinal Cancer Stem Cell Proliferation

Ting Fu; Sally Coulter; Eiji Yoshihara; Tae Gyu Oh; Sungsoon Fang; Fritz Cayabyab; Qiyun Zhu; Tong Zhang; Mathias Leblanc; Sihao Liu; Mingxiao He; Wanda Waizenegger; Emanuel Gasser; Bernd Schnabl; Annette R Atkins; Ruth T Yu; Rob Knight; Christopher Liddle; Michael Downes; Ronald M Evans

doi:10.1016/j.cell.2019.01.036

FXR Regulates Intestinal Cancer Stem Cell Proliferation

Cell. 2019 Feb 21;176(5):1098-1112.e18. doi: 10.1016/j.cell.2019.01.036.

Authors

Ting Fu¹, Sally Coulter², Eiji Yoshihara¹, Tae Gyu Oh¹, Sungsoon Fang³, Fritz Cayabyab¹, Qiyun Zhu⁴, Tong Zhang⁵, Mathias Leblanc¹, Sihao Liu¹, Mingxiao He¹, Wanda Waizenegger¹, Emanuel Gasser¹, Bernd Schnabl⁶, Annette R Atkins¹, Ruth T Yu¹, Rob Knight⁷, Christopher Liddle², Michael Downes⁸, Ronald M Evans⁹

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: downes@salk.edu.
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: evans@salk.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bile Acids and Salts / metabolism
Cell Line
Cell Proliferation / genetics
Colorectal Neoplasms / metabolism
Deoxycholic Acid / metabolism
Gene Expression Regulation, Neoplastic / genetics
Humans
Intestinal Neoplasms / genetics
Intestinal Neoplasms / metabolism*
Intestines
Liver
Mice
Mice, Inbred C57BL
Neoplastic Stem Cells / metabolism*
Neoplastic Stem Cells / physiology
Organoids / metabolism
Receptors, Cytoplasmic and Nuclear / genetics
Receptors, Cytoplasmic and Nuclear / metabolism*
Risk Factors
Signal Transduction
Taurocholic Acid / analogs & derivatives
Taurocholic Acid / metabolism
Wnt Signaling Pathway / genetics
Wnt Signaling Pathway / physiology

Substances

Bile Acids and Salts
Receptors, Cytoplasmic and Nuclear
Deoxycholic Acid
farnesoid X-activated receptor
tauromuricholic acid
Taurocholic Acid

Abstract

Publication types

MeSH terms

Substances

Grants and funding