@article{270a7aab2041448cb2b200467ed6149e,
title = "FXR Regulates Intestinal Cancer Stem Cell Proliferation",
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.",
keywords = "BA-FXR axis, Lgr5 intestinal stem cells, colon cancer progression, genetic and dietary risk factors",
author = "Ting Fu and Sally Coulter and Eiji Yoshihara and Oh, {Tae Gyu} and Sungsoon Fang and Fritz Cayabyab and Qiyun Zhu and Tong Zhang and Mathias Leblanc and Sihao Liu and Mingxiao He and Wanda Waizenegger and Emanuel Gasser and Bernd Schnabl and Atkins, {Annette R.} and Yu, {Ruth T.} and Rob Knight and Christopher Liddle and Michael Downes and Evans, {Ronald M.}",
note = "Funding Information: We thank Z. Wei and W. Fan for scientific discussion; Y. Dai, J. Alvarez, H. Juguilon, L. Chong, and B. Collins for technical assistance; C. O{\textquoteright}Connor and C. Fitzpatrick in Salk FACS core and UCSD FACS core for sorting the cells; David O{\textquoteright}Keefe for editorial assistance; and L. Ong and C. Brondos for administrative assistance. This work was funded by grants from the NIH ( DK057978 , HL105278 , HL088093 , and ES010337 ), the Cancer Center ( CA014195 ), National Health and Medical Research Council of Australia Project grants ( 512354 and 632886 to C.L. and M.D.), the Leona M. and Harry B. Helmsley Charitable Trust ( 2017PG-MED001 ), and Samuel Waxman Cancer Research Foundation and Ipsen/Biomeasure . T.F. is supported by a Hewitt Medical Foundation Fellowship and a Salk Alumni Fellowship. S.F is funded by the Korean government (Ministry of Science and ICT) for Korea Mouse Phenotyping Project ( 2013M3A9D5072550 ), Bio and Medical Technology Development program ( 2017M3A9F3046538 ), and Basic Science Research Program ( NRF-2018R1A2B6003447 ). R.M.E. and M.D. are supported, in part, by a Stand Up to Cancer Dream Team Translational Cancer Research grant and a Program of the Entertainment Industry Foundation ( SU2C-AACR-DT-20-16 ). R.M.E is an investigator of the Howard Hughes Medical Institute and March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute. Funding Information: We thank Z. Wei and W. Fan for scientific discussion; Y. Dai, J. Alvarez, H. Juguilon, L. Chong, and B. Collins for technical assistance; C. O'Connor and C. Fitzpatrick in Salk FACS core and UCSD FACS core for sorting the cells; David O'Keefe for editorial assistance; and L. Ong and C. Brondos for administrative assistance. This work was funded by grants from the NIH (DK057978, HL105278, HL088093, and ES010337), the Cancer Center (CA014195), National Health and Medical Research Council of Australia Project grants (512354 and 632886 to C.L. and M.D.), the Leona M. and Harry B. Helmsley Charitable Trust (2017PG-MED001), and Samuel Waxman Cancer Research Foundation and Ipsen/Biomeasure. T.F. is supported by a Hewitt Medical Foundation Fellowship and a Salk Alumni Fellowship. S.F is funded by the Korean government (Ministry of Science and ICT) for Korea Mouse Phenotyping Project (2013M3A9D5072550), Bio and Medical Technology Development program (2017M3A9F3046538), and Basic Science Research Program (NRF-2018R1A2B6003447). R.M.E. and M.D. are supported, in part, by a Stand Up to Cancer Dream Team Translational Cancer Research grant and a Program of the Entertainment Industry Foundation (SU2C-AACR-DT-20-16). R.M.E is an investigator of the Howard Hughes Medical Institute and March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = feb,
day = "21",
doi = "10.1016/j.cell.2019.01.036",
language = "English (US)",
volume = "176",
pages = "1098--1112.e18",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "5",
}