LI
LABORATORY

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Research Focus

The Li laboratory is studying Wnt/β-catenin signaling in tumor formation and progression with the ultimate goal of developing therapeutic agents for Wnt-dependent cancers. One of the focus areas in his laboratory is to define the roles of Wnt co-receptor LRP6 and its regulators including R-spondin proteins in tumorigenesis, metastasis and drug resistance. Another major focus of his research is to identify and develop small molecule Wnt inhibitors for cancer therapy. In particular, Dr. Li is collaborating with medicinal chemists and computational chemists at Southern Research to identify and develop small molecule inhibitors of LRP6 and frizzled proteins.

Rspo-LRP6 signaling in breast cancer

Wnt/β-catenin signaling plays an important role in embryonic development and can lead to tumor formation when aberrantly activated. Wnt proteins bind to the low-density lipoprotein receptor-related protein5/6 (LRP5/6) and Frizzled (Fzd) to activate the Wnt/β-catenin signaling pathway. The R-spondin (Rspo) protein family is another group of secreted proteins that can strongly enhance Wnt/β-catenin signaling. LGR4 (leuc ine-rich repeat-containing G-protein-coupled receptor 4), LGR5 and LGR6 are receptors for Rspos. The cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt/β-catenin signaling by promoting the turnover of Fzd and LRP6. It is well established that Rspo proeins interact with the extracellular domain of ZNRF3/RNF43 and induce the association between ZNRF3/RNF43 and LGR4/5/6, which results in membrane clearance of ZNRF3/RNF43 and thereby stabilizes LRP6 and Fzd for a greater Wnt response.

We have reported for the first time that LRP6 is readily expressed in several human cancer cell lines and human malignant tissues, and that stable expression of LRP6 in human cancer cells alters subcellular β-catenin distribution, activates Wnt/β-cli-lab-2atenin signaling and promotes cancer cell proliferation in vitro and tumor growth in vivo. Furthermore, we generated transgenic mice overexpressing LRP6 in mammary epithelial cells driven by the mouse mammary tumor virus (MMTV) promoter, and demonstrated that MMTV-LRP6 transgenic mice develop hyperplasia in their mammary glands due to LRP6-mediated Wnt/β-catenin signaling. Recent studies indicate that Wnt/β-catenin signaling is particularly activated in triple negative breast cancer (TNBC), such that LRP6 was found to be up-regulated in TNBC. While Wnt proteins have been identified for more than 30 years, no Wnt ligand overexpression has yet been directly associated with human cancer. Our preliminary studies point out that dysregulation of Rspo protein expression and function may directly impact Wnt/β-catenin signaling in breast cancer. Therefore, we hypothesized that Rspo proteins are responsible for driving Wnt/β-catenin signaling over-activation in human breast cancer, and overexpression of Rspo proteins induces mammary tumorigenesis.

The major goals of the current project are (i) To determine whether Rspo proteins are frequently up-regulated in human breast cancer tissues; and (ii) To study the importance of each Rspo protein in the activation of Wnt/β-catenin signaling in breast cancer cells; and (iii) To define the roles of Rspo proteins in breast cancer cell proliferation, apoptosis, stemness and tumor growth. These studi
es will provide new insights into how Wnt/β-catenin signaling is activated in breast cancer, and will provide a framework for the design of therapeutic strategies aimed at modulating Wnt/β-catenin signaling in human breast cancer patients.

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Wnt inhibitors for cancer therapy

 

Activation of Wnt/β-catenin signaling has been found to be important for both initiation and progression of cancers of different tissues. Disruption of Wnt/β-catenin signal represents an opportunity for rational cancer chemoprevention and therapy. Our laboratory has been actively working on drug discovery targeting the Wnt/β-catenin signaling pathway for cancer therapy.

Mesd is a specialized chaperone for Wnt co-receptors LRP5 and LRP6. We have demonstrated that recombinant Mesd protein binds to LRP5/6 with a high affinity at the cell surface and is a universal inhibitor of LRP5/6 ligands. Recombinant Mesd protein not only blocks binding of Wnt antagonists Dkk1 and Sclerostin to LRP5/6 but also inhibits Wnt- and Rspo-induced Wnt/β-catenin signaling in LRP5- and LRP6-expressing cells. More importantly, we demonstrated that recombinant Mesd protein and its C-terminal peptides are able to suppress LRP6 phosphorylation, block Wnt/β-catenin signaling in breast and prostate cancer cells, and inhibit cancer cell proliferation in vitro and tumor growth in vivo.

Niclosamide is an FDA approved antihelminthic drug. We recently demonstrated that niclosamide suppresses Wnt/β-catenin signaling through promoting Wnt co-receptor LRP6 degradation in cancer cells, and displays an excellent anti-cancer activity in vitro. However, niclosamide exerts its antiparasitic activity in the intestinal lumen and is poorly absorbed from the gastrointestinal tract, which could limit the application of niclosamide as an anticancer agent. Collaborating with medicinal chemists at Southern Research, we are conducting studies to identify novel derivatives of niclosamide with improved bioavailability as clinical candidates for cancer therapy.

Of the 10 members of the Fzd family, Fzd7 is the most important member governing cancer development and progression, and is a promising therapeutic target in cancer. Collaborating with Dr. Wei Zhang at Southern Research, we are performing molecular simulations, model development, virtual screening and biological evaluations for small molecule inhibitors of Fzd7. The identified Fzd7 inhibitors will represent promising leads for the development of novel chemopreventive and chemotherapeutic agents for Wnt-dependent cancers. They will also be important pharmacological tools for studying the mechanisms and role of Fzd7-mediated Wnt/β-catenin signaling in various physiological and disease processes.

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Yonghe Li, Ph.D.

Advanced Research Scientist, Department of Oncology

Yonghe Li, Ph.D., is an advanced research scientist in Southern Research’s Department of Oncology. He also currently serves as an adjunct associate professor of pharmacology and toxicology at the University of Alabama at Birmingham (UAB) and is a member of the UAB Comprehensive Cancer Center. [ Read Full Bio Here ]

Lab Members

Wenyan Lu

Wenyan Lu

Biologist

Wenyan Lu, Biologist, has substantial experience conducting experiments on Wnt/β-catenin signaling in cancer cells and drug discovery for cancer therapy. She obtained her Bachelor of Medicine in Acupuncture and Moxibustion from Shanghai University of Traditional Chinese Medicine, China. She joined Southern Research in 2006 from Washington University School of Medicine, St. Louis, where she was a research technician.



How To Work With Us

 

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