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

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

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. The progression of colorectal cancer is fueled by the bile-acid-dependent inhibition of the receptor FXR.

Original languageEnglish (US)
Pages (from-to)1098-1112.e18
JournalCell
Volume176
Issue number5
DOIs
StatePublished - Feb 21 2019

Keywords

  • BA-FXR axis
  • Lgr5 intestinal stem cells
  • colon cancer progression
  • genetic and dietary risk factors

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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