Faculty

JING YANG

Assistant Professor of Pharmacology and Pediatrics

TEL: 858-534-1994

FAX: 858-534-7390

email: jingyang@ucsd.edu

Ph.D., Duke University

Key Words: tumor metastasis, Epithelial-Mesenchymal Transition (EMT), Twist, functional genomics, mouse genetics.

Tumor metastasis is a complex, multi-step process by which cancer cells spread from a primary site to distant organs and establish secondary tumors. Although tumor metastasis causes over 90% of cancer deaths, its molecular basis is largely unknown. The research in my laboratory aims to uncover the genes and the signaling pathways responsible for tumor metastasis. Our experimental approaches combine molecular biology tools, mouse tumor models, functional genomics and in vivo imaging techniques.

We have explored a unique mouse breast cancer metastasis model to identify key regulators of tumor metastasis. Our studies discovered that the Twist transcription factor, a master regulator of early embryonic morphogenesis, is essential for the ability of breast tumor cells to metastasize from the mammary gland to the lung. We further demonstrated that Twist contributes to tumor invasion and metastasis by activating a latent developmental program termed an epithelial-mesenchymal transition (EMT). Ectopic expression of Twist resulted in loss of E-cadherin-mediated cell-cell adhesion, activation of mesenchymal markers, and induction of cell motility. Recently, our and several other studies reported the involvement of Twist and the EMT program in various human malignancies, including breast cancers, gastric cancers, melanomas and neuroblastomas.

Currently, our research focuses on the following areas:

1) The Molecular Machinery: Twist, as a key player in tumor metastasis, may exploit several transcription targets to provoke EMT and other aspects of migration and invasion. We are using genomics, bioinformatics, and biochemical approaches to dissect the signaling and effector pathways that link Twist to EMT and tumor metastasis. We also plan to test the involvement of these signaling pathways in clinical human cancers.
2) The Dynamic Action: The in vivo role of EMT in tumor metastasis is still highly debated. Clinical observations show that the majority of human carcinoma metastases present an epithelial morphology in distant organs. We propose that carcinoma cells undergo EMT to invade and disseminate. Once reaching distant organs, these mesenchymal cells will reverse to an epithelial identity in order to regain proliferating ability. We have established mouse tumor models to determine how Twist and EMT contribute to tumor metastasis in vivo.
3) The Inducing Signals: The ability of carcinoma cells to undergo EMT and metastasize depends on both their genetic/epigenetic alternations and the environmental cues they receive. Several signaling pathways, including TGF-beta, Wnt, and Notch, are involved in activating cell migration and tissue rearrangement during normal development. We are very interested in exploring the roles of such signals in inducing Twist, EMT and tumor metastasis.
4) The Novel Players: Our previous study identified a number of new candidate genes involved in tumor metastasis. We will explore their biological functions in tumor metastasis using cell culture models, mouse tumor models, and clinical human tumor samples.

Selected Publications

Gupta PB, Mani SA, Yang J, Hartwell K, Weinberg RA. (2005) The Evolving Portrait of Cancer Metastasis. Cold Spring Harbor Symposia on Quantitative Biology 70:291-7.

Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA. (2004). Twist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor Metastasis. Cell 117(7): 927-939.

Yang J, Song H, Walsh S, Bardes ESG, Kornbluth S. (2001). Combinatorial control of cyclin B1 nuclear trafficking through phosphorylation at multiple sites. Journal of Biological Chemistry, 276(5): 3604-3609.

Yang J, Winkler K, Yoshida M, Kornbluth S. (1999). Maintenance of G2 arrest in the Xenopus oocyte: a role for 14-3-3-mediated inhibition of Cdc25 nuclear import. EMBO Journal, 18, 2174-2183.

Moore JD, Yang J, Traunt R, Kornbluth S. (1999). Nuclear import of Cdk/Cyclin complexes: identification of distinct mechanisms for import of Cdk2/Cyclin E and Cdc2/Cyclin B1. Journal of Cell Biology, 144: 213-224.

Yang J, Kornbluth S. (1999). All aboard the Cyclin train: subcellular trafficking of Cyclins and their Cdk partners. Trends in Cell Biology, 9: 207-210.

Hinchcliffe EH, Thompson EA, Miller FJ, Yang J, and Sluder G. (1999). Nucleo-cytoplasmic interaction in the control of nuclear envelope breakdown and entry into mitosis in the sea urchin zygote. Journal of Cell Science, 112: 1139-1148.

Yang J, Bardes ESG, Moore JD, Brennan J, Powers MA, and Kornbluth S. (1998). Control of Cyclin B1 localization through regulated binding of the nuclear export factor, CRM1. Genes & Development, 12: 2131-2143.

Crenshaw DJ*, Yang J*, Means AR, and Kornbluth S. (1998). The mitotic peptidyl-prolyl isomerase, Pin1 interacts with key regulators of Cdc2/Cyclin B. EMBO Journal, 17, 1315-1327.