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Manipulation of focal Wnt activity via synthetic cells in a double‐humanized zebrafish model of tumorigenesis
Author(s) -
Wang Lei,
Long Jiang,
Chen Huan,
Sun Shaoyang,
Lv Kunpeng,
Li Qiang,
Wang Xu
Publication year - 2021
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.33458
Subject(s) - wnt signaling pathway , zebrafish , jurkat cells , dkk1 , biology , microbiology and biotechnology , carcinogenesis , peripheral blood mononuclear cell , cancer research , humanized mouse , in vivo , signal transduction , t cell , immunology , cancer , in vitro , biochemistry , gene , immune system , genetics
The canonical Wnt signaling pathway is activated in numerous contexts, including normal and cancerous tissues. Here, we describe a synthetic cell‐based therapeutic strategy that inhibits aberrant Wnt activity in specific focuses without interfering with the normal tissues in vivo. As a proof of principle, we generated a triple transgenic zebrafish liver cancer model that conditionally expressed human MET and induced ectopic Wnt signaling in hepatocytes. Then, we generated a customized synthetic Notch receptor (synNotch) cascade to express Wnt inhibitor DKK1 in Jurkat T cells and human peripheral blood mononuclear cells (PBMCs) after recognizing MET as antigen. After that, the synNotch PBMCs were sorted and microinjected into different tissues of the zebrafish model. In MET‐expressing cancerous liver tissues, the injected cells expressed DKK1 and inhibited the local proliferation and Wnt activity; while in the yolk sac without MET, the injected cells remained inactive. Overall, our studies revealed the use of synthetic cells with antigen receptors to improve the spatiotemporal accuracy of anti‐Wnt therapy, and proposed that the genetically humanized zebrafish model may serve as a small‐scale and highly optically accessible platform for the functional evaluation of human synthetic cells.