Shirley Ting Fu

Focus Groups

Cancer Biology and Immunology/Immunopathology

Education

PhD, The University of Illinois at Urbana-Champaign

Postdoc, Salk Institute of Biological Science

Research Summary

Fu laboratory mainly studies how nuclear receptors sense environmental clues and regulate Gastrointestinal (GI) homeostasis in healthy and disease states. Specifically, I am interested in how dietary and microbial induced bile acids are sensed by Farnesoid X Receptor (FXR) and dynamically affect intestinal development, differentiation, and inflammation, focusing on colorectal cancer (CRC) and intestinal bowel disease (IBD).

Research Detail

Gastrointestinal diseases, including Colorectal Cancer (CRC) and inflammatory bowel disease, are alarmingly prevalent. However, in-depth investigation of gut metabolism, physiology, and immunology is limited, especially the dynamic communications between host and microbiota. The overarching goal of my research is to understand how nutritional signals (such as bile acids, BAs) are sensed by nuclear receptors (such as FXR) in intestinal epithelium and mucosal layer, dynamically change in health and disease states, and actively communicate with gut microbiome through secondary metabolites (such as novel microbial BAs).

My research focuses on the novel role of FXR in the intestine. The first seminal work I did demonstrated the novel role of FXR in intestinal stem cells in colon cancer (CRC). I discovered that the convergence of dietary factors (high-fat diet, HFD) and dysregulated WNT signaling (APC mutation) independently alters BA profiles but could converge on BA-FXR axis to drive malignant transformations in cancer stem cells and promote an adenoma-to-adenocarcinoma progression. The second breakthrough discovery is about how innate lymphoid cells (ILCs) sense BAs and FXR mediates ILC-intrinsic responses to intestinal inflammation. The third landmark study is a multi-omics collaborative work to identify a class of novel microbial modified, gut-specific, amino acid-conjugated BAs (AA-BAs), which potent ligand for the FXR and membrane BAs receptor, TGR5. Certain AA-BAs and their corresponding gut bacteria are responsible for adenoma-to-adenocarcinoma progression in CRC. These findings identify FXR as a master regulator of intestinal physiology and immunology and a potential therapeutic target in colon cancer and inflammatory bowel diseases. Thus, my 5-year research goal is to focus on the function of the BAs-FXR axis in host physiology and immunity as a converging point of the genetic, dietary, and microbial risk factors of gastrointestinal diseases, which is a natural extension of my Postdoc research work.

Two projects currently carried out in my lab also focus on intestinal stem cell biology and mucosal immunology. In the mucosal immunology project, we found that inflammation-induced epithelial abnormalities compromised FXR signaling and altered BAs profile in colitis-induced colon cancer model. Moreover, gut macrophage intrinsic FXR can sense these aberrant BAs, leading to secretion of pro-inflammatory cytokines, which promotes ISCs’ proliferation. Notably, reactivation of FXR signaling reduced intestinal inflammation and tumorigenesis by suppressing pro-inflammatory responses in gut macrophages and Th17 cells. Mechanistically, we uncovered that FXR regulates gut macrophage’s recruitment, polarization, maturation, and crosstalk with Th17 cells. In the stem cell project, we revealed that FXR transcriptionally regulates TLE3, a transducin-like enhancer of split3, a transcriptional repressor of the beta-catenin/TCF4 complex. Gradually reduced expression of FXR in colon cancer fails to activate TLE3 expression, which in turn triggering Wnt/beta-catenin activation. Loss of FXR in intestinal stem cells also led to aberrant cell proliferation in APCmin mice.

Publications

1. Ting Fu, Sally Coulter, Eiji Yoshihara, Tae Gyu Oh, Sungsoon Fang, Fritz Cayabyab, Qiyun Zhu, Michael Downes*, Ronald M. Evans*, et al. FXR regulates intestinal stem cell proliferation. VOLUME 176, ISSUE 5, P1098-1112.E18, FEBRUARY 21, 2019, Cell.
2. Tae Gyu Oh, Susy Kim, Cyrielle Caussy, Ting Fu,…Michael R. Downes, Ronald M. Evans,* and Rohit Loomba,*et al. A Universal Gut Microbiome-Derived Signature for Predicting NAFLD-Cirrhosis Externally Validated with Geographically Independent Cohorts. Cell Metabolism.
3. Robert A. Quinn, Alexey V. Melnik, Alison Vrbanac, Ting Fu, …Ronald M. Evans, Victor Nizet, Rob Knight, and Pieter C. Dorrestein, et al. Global Chemical Impacts of the Microbiome Include Unique Bile Acid Conjugates that Stimulate FXR. Nature, 2020 Mar; 579(7797):123-129.
4. Ting Fu*, Youngchea Kim*, Dong-Hyun Kim, Sunmi Seok, Kelly Suino-Powell, H. Eric Xu, Byron Kemper and Jongsook Kim Kemper. FXR primes the liver for intestinal FGF15 signaling by transient induction of βklotho. Molecular Endocrinology, 2015 Oct 23;
5. Sunmi Seok*, Ting Fu*, Sung-E Choi, Yang Li, Rong Zhu, Subodh Kumar, Xiaoxiao Sun, Gyesoon Yoon, Yup Kang, Wenxuan Zhong, Jian Ma, Byron Kemper, and Jongsook Kim Kemper. Transcriptional regulation of autophagy by an FXR/CREB1 axis. Nature, 516, 108–111, 2014.
6. Ting Fu, Sunmi Seok, Sung-E Choi, Zhang Huang, Kelly Suino-Powell, H. Eric Xu, Byron Kemper, and Jongsook Kim Kemper. MiR-34a inhibits beige and brown fat formation in obesity in part by suppressing adipocyte FGF21 signaling and SIRT1 function. Molecular and Cellular Biology, 2014, Nov 15; 34(22):4130-42.
7. SungE Choi, Ting Fu, Sunmi Seok, Dong-Hyun Kim, Eunkyung Yu, Kwan-woo Lee, Yup Kang, Xiaoling Li, Byron Kemper, Jongsook Kim Kemper. Elevated microRNA-34a in obesity reduces NAD+ levels and SIRT1 activity by directly targeting NAMPT. Aging Cell. 2013 Dec; 12(6):1062-72.
8. Ting Fu, SungE Choi, Dong-Hyun Kim, Sunmi Seok, Kelly Suino-Powell, H. Eric Xu, and Jongsook Kim Kemper. Aberrantly elevated miR-34a in obesity attenuates hepatic responses to FGF19 by targeting a membrane coreceptor β-Klotho. PNAS, 2012 Oct 2; 109(40):16137-42.
9. Xingchen Dong*, Chunmiao Cai*, Ting Fu#. FXR suppress colorectal cancer by inhibiting the Wnt/β-catenin pathway via activation of TLE3. Genes and Diseases, 2022. doi: 10.1016/j.gendis.2022.09.006

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