Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • We show here that FXR is a point of

    2021-09-18

    We show here that FXR is a point of convergence of heredity (H) and environmental (E) risk factors for CRC (re the Tomasetti and Vogelstein model). Our studies demonstrate that the APC mutation and high-fat diet independently and cooperatively increase the BA pool that results in the repression of FXR signaling in intestinal stem cells. Mechanistically, we identify T-βMCA and DCA, natural FXR antagonists upregulated in APCmin/+ mice, as potent drivers of CSC proliferation and capable of inducing DNA damage. The high rate of intestinal stem cell divisions and the associated increased risk for DNA replication (R) errors has been implicated in the incidence of CRC (Tomasetti et al., 2017, Tomasetti and Vogelstein, 2015). Indeed, replacement of the intestinal epithelium requires the continuous renewal and differentiation of stem cells, a process regulated by the WNT signaling gradient and dependent upon the crypt-villus structure. Erosion of this structure not only disrupts the WNT gradient, but increases the exposure of crypt-resident Lgr5+ Castanospermine to diet-induced cues including fatty acids and BAs, thereby increasing the possibility for malignant transformation. These findings support the importance of FXR in maintaining the crypt-villus structure, gut homeostasis, and crypt integrity, as well as demonstrate how disabled FXR signaling contributes to the “bottom-up” model for CRC progression (Figures 7H and S7D). Early screening combined with advances in surgical and adjuvant therapies have improved survival rates for CRC, but additional pharmacologic interventions are needed (Kuipers et al., 2015). Our findings identify FXR in the cancer stem cells as a potential therapeutic target for treating or preventing CRC. Indeed, we show that FexD, a gut-biased FXR agonist, delayed tumor progression and profoundly increased survival in APCmin/+ mouse models of adenoma and adenocarcinoma. Histological examination revealed that FexD impedes tumor progression at multiple stages: hyperplasia, micro-adenoma, adenoma, and adenocarcinoma (Figure 7C), emphasizing the critical role of FXR in regulating CSCs. FXR actions in additional intestinal cell types, such as endocrine cells, and its interaction with other signaling pathways may additionally contribute to its propitious role in maintaining crypt-villus homeostasis (Gregorieff et al., 2015, Rodríguez-Colman et al., 2017, Sato et al., 2011). Thus, the re-establishment of FXR signaling not only restricts aberrant Lgr5+ stem cell proliferation but also promotes gut health including restoring the intestinal barrier (De Gottardi et al., 2004, Modica et al., 2008) and BA homeostasis (Fu et al., 2012, Fu et al., 2016a, Parséus et al., 2017; Figure 7D). Beyond its well-established role in regulating cytotoxicity of hydrophobic BAs, our study highlights the role of FXR in restricting the tumorigenesis of Lgr5+ cells, which mediate the key adenoma-to-adenocarcinoma transformation. As one FXR agonist (OCA) has recently been approved and others are advancing in clinical trials for liver disease, a rapid translation of these findings into CRC patients is foreseeable.
    STAR★Methods
    Acknowledgments 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.