Rb Tumor Suppressor, Control of Cell Proliferation and Differentiation
1) Novel approaches to target the loss of tumor suppressors in cancers
The success of cancer therapies generally depend on their ability to target certain unique requirements of the cancer cells that are distinct from those of the normal cells. Current targeted cancer therapies at different stages of development mostly focus on inhibiting the deregulated oncogenic pathways kinases in cancers. In addition to deregulated oncogenic activation, cancer cells also often have inactivation of tumor suppressors. However such knowledge has yet to be exploited to develop targeted cancer therapies due to a lack of approaches to restore the lost tumor suppressor function in all the cancer cells and a lack of knowledge about the genes that are synthetic lethal with the lost tumor suppressors. While it is possible to carry out genome-wide RNAi screen to identify genes that are synthetic lethal with Rb using cell culture assays, such screen will depend largely on the particular culture conditions and may or may not reflect the in vivo situations.
Rb is a tumor suppressor that is often lost in cancers. Because the Rb/E2F pathway is highly conserved between flies and mammalian systems, we hypothesize that genes that are synthetic lethal with loss of Rb will be conserved between the two systems as well. In a genetic screen for genes that can modulate the consequences of Rb loss, we found that mutation of gig, the Drosophila TSC2 homolog, show synergistically increased cell death with loss of Rb. Interestingly, knockdown of TSC2 in human cancer cells blocks cancer cell growth and induced cell death dependent on the Rb status, suggesting that TSC2 can potentially be used to specifically target Rb mutant cancers.
Research in the lab include further characterization of the mechanisms of synergistic cell death induction, identification of genes/pathways/chemical inhibitors that can enhance the specific cell death induction by TSC2 knockdown, developing assays to screen for small molecule inhibitors of TSC2 function, and carry out additional genetic screen to identify additional potential targets.
2) Molecular mechanisms that coordinate the control of cell proliferation and differentiation during normal development
We use the Drosophila developing eye as a model system to elucidate mechanisms by which developmental mechanisms coordinate cell proliferation and differentiation. In third instar eye discs, the morphogenetic furrow (MF), which is marked by an indentation in the eye disc, moves from posterior of the eye disc to the anterior. Cells anterior to the MF are asynchronously proliferating, which become cell cycle arrest in G1 in the MF. Photoreceptor differentiation initiates in the MF and the first photoreceptor determined is R8. R8 photoreceptor differentiation is controlled by the Atonal (Ato), a bHLH protein initially expressed in the MF and then restricted to the future R8 cells. Therefore one project in the lab is to elucidate the regulation of Ato expression, which is regulated by retinal determination genes and developmental signaling pathways.
Cells in the MF and the differentiating photoreceptor clusters are arrested in G1. immediately posterior to the MF, cells not in the photoreceptor clusters undergo a synchronous round of cell cycle called second mitotic wave (SMW). Notch and EGFR signaling plays critical roles in controlling photoreceptor differentiation or cell proliferation. We are investigating the molecular mechanisms by which these developmental signaling pathways coordinate cell proliferation and differentiation.
B.S. - Biochemistry
Ph.D. - Biochemistry and Molecular Biology
Harvard Medical School/MGH Cancer Center
postdoc - Molecular Oncology
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Zhang T, Hsu FN, Xie XJ, Li X, Liu M, Gao X, Pei X, Liao Y, Du W, Ji JY. Reversal of hyperactive Wnt signaling-dependent adipocyte defects by peptide boronic acids. Proc Natl Acad Sci U S A. 2017 09 05; 114(36):E7469-E7478.
Loss of histone deacetylase HDAC1 induces cell death in Drosophila epithelial cells through JNK and Hippo signaling.
Zhang T, Sheng Z, Du W. Loss of histone deacetylase HDAC1 induces cell death in Drosophila epithelial cells through JNK and Hippo signaling. Mech Dev. 2016 08; 141:4-13.
ESCRT-0 complex modulates Rbf-mutant cell survival by regulating Rhomboid endosomal trafficking and EGFR signaling.
Sheng Z, Yu L, Zhang T, Pei X, Li X, Zhang Z, Du W. ESCRT-0 complex modulates Rbf-mutant cell survival by regulating Rhomboid endosomal trafficking and EGFR signaling. J Cell Sci. 2016 05 15; 129(10):2075-84.
Red ginseng and cancer treatment.
Wang CZ, Anderson S, DU W, He TC, Yuan CS. Red ginseng and cancer treatment. Chin J Nat Med. 2016 Jan; 14(1):7-16.
Groucho restricts rhomboid expression and couples EGFR activation with R8 selection during Drosophila photoreceptor differentiation.
Zhang T, Du W. Groucho restricts rhomboid expression and couples EGFR activation with R8 selection during Drosophila photoreceptor differentiation. Dev Biol. 2015 Nov 15; 407(2):246-55.
American ginseng significantly reduced the progression of high-fat-diet-enhanced colon carcinogenesis in Apc (Min/+) mice.
Yu C, Wen XD, Zhang Z, Zhang CF, Wu X, He X, Liao Y, Wu N, Wang CZ, Du W, He TC, Yuan CS. American ginseng significantly reduced the progression of high-fat-diet-enhanced colon carcinogenesis in Apc (Min/+) mice. J Ginseng Res. 2015 Jul; 39(3):230-7.
TRAIL pathway is associated with inhibition of colon cancer by protopanaxadiol.
Zhang Z, Li Z, Wu X, Zhang CF, Calway T, He TC, Du W, Chen J, Wang CZ, Yuan CS. TRAIL pathway is associated with inhibition of colon cancer by protopanaxadiol. J Pharmacol Sci. 2015 Jan; 127(1):83-91.
The homeodomain of Eyeless regulates cell growth and antagonizes the paired domain-dependent retinal differentiation function.
Tanaka-Matakatsu M, Miller J, Du W. The homeodomain of Eyeless regulates cell growth and antagonizes the paired domain-dependent retinal differentiation function. Protein Cell. 2015 Jan; 6(1):68-78.
American ginseng attenuates azoxymethane/dextran sodium sulfate-induced colon carcinogenesis in mice.
Yu C, Wen XD, Zhang Z, Zhang CF, Wu XH, Martin A, Du W, He TC, Wang CZ, Yuan CS. American ginseng attenuates azoxymethane/dextran sodium sulfate-induced colon carcinogenesis in mice. J Ginseng Res. 2015 Jan; 39(1):14-21.
Chemopreventive effects of oplopantriol A, a novel compound isolated from Oplopanax horridus, on colorectal cancer.
Zhang Z, Yu C, Zhang CF, Wu XH, Wen XD, Anderson S, Du W, Huang WH, Li SP, Wang CZ, Yuan CS. Chemopreventive effects of oplopantriol A, a novel compound isolated from Oplopanax horridus, on colorectal cancer. Nutrients. 2014 Jul 18; 6(7):2668-80.
Cancer Research Foundation Fletcher Scholar
2006 - 2008
Leukemia & Lymphoma Society Scholar
2003 - 2008
Sydney Kimmel Scholar
1998 - 2000