BBS Faculty Member - Jean Zhao

Jean Zhao

Department of Biological Chemistry & Molecular Pharmacology, HMS

Dana Farber Cancer Institute
Smith Building, Room 936A
450 Brookline Ave.
Boston, MA 02215
Tel: 617-632-2932
Fax: 617-632-3709
Email: jean_zhao@dfci.harvard.edu
Lab Members: 7 postdoctoral fellows, 3 graduate students (1 visiting), 3 technicians
Visit my lab page here.



We are interested in how kinases in general, and phosphatidylinositol 3-kinases (PI3K) in particular, control malignant transformation. The work of our laboratory integrates molecular biology, tissue engineering and novel mouse models of human cancer to study oncogenic alterations in kinases that are involved in tumor formation and metastasis. In addition to our unique genetically engineered mouse models, we have developed a number of additional experimental systems, including, synthetic human tumors, and kinome-wide libraries of activated kinases to elucidate the mechanisms by which kinases function in cancer.

The PI3K pathway is a key signal transduction system that links oncogenes and multiple receptors to many essential cellular functions, which is tightly regulated by PI3Ks and the tumor suppressor PTEN. This pathway is perhaps the most commonly activated signaling pathway in human cancer, therefore presenting both an opportunity and a challenge for cancer therapy. Studies in our group using genetic engineered mouse models of tissue-specific ablation of PIK3CA or PIK3CB begin to reveal distinct roles of these two isoforms in cellular signaling, metabolism, development and tumorigenesis, providing the framework and rationale for targeting selective isoforms of PI3K in cancer. We continue to define how these isoforms of PI3K function in different tumor types and tissues, and their individual and collective contributions to transformation. More importantly, we are striving to understand the underlying cellular and molecular pathways and programs that protect tumors with aberrant activation of PI3K from PI3K-targeted therapy to overcome the major challenge of resistance and improve therapeutic efficacy.

In parallel, we take kinome-wide approaches to the systematic study kinase signaling in oncogenic transformation. We constructed the first kinome-wide libraries of “gain of function” human kinases and used this system in a number of functional genetic screens leading to the identification of novel oncogenic kinases, such as IKBKE and MAP3K8. We also take kinome-wide “loss of function” approaches to decipher the process of transformation. For example, we identified SIK1 as a novel kinase that regulates p53 in response to loss of adhesion. We demonstrated that SIK1 couples LKB1 to p53-dependent anoikis and suppression of metastasis, thus establishing the LKB1-SIK1-p53 axis as a potentially important pathway in metastatic disease. Our recent discovery that MELK is essential for the survival and cell division of cancer cells, but not normal cells, has revealed a potential “Achilles’ heel” in cancer, representing a promising molecular target in cancer treatment.

In summary, ongoing and future studies in our laboratory integrate biochemistry, cell biology, novel mouse genetic models, and chemical biology to study kinase signaling pathways in order to translate fundamental mechanistic findings into novel therapeutic strategies. Our research interests and unique integrated approaches allow us to continue to work at the forefront of cancer biology and foster innovative and productive science.



Last Update: 6/20/2014



Publications

Liu P, Cheng H, Santiago S, Raeder M, Zhang F, Isabella A, Yang J, Semaan DJ, Chen C, Fox EA, Gray NS, Monahan J, Schlegel R, Beroukhim R, Mills GB, Zhao JJ. Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms. Nature Medicine, in press (NIHMS297795)

Sopasakis VR, Liu P, Suzuki R, Kondo T, Winnay J, Tran TT, Asano T, Smyth G, Sajan MP, Farese R.V, Kahn C.R,
Zhao J.J. Specific roles of the p110a isoform of phosphatidylinsositol 3-kinase in hepatic insulin signaling and metabolic regulation. Cell Metab. 2010 Mar 3;11(3):220-30.

Cheng H., Liu P., Wang ZC, Zou L, Santiago S, Garbitt V, Gjoerup OV, Iglehart JD, Miron A, Richardson AL, Hahn WV, and
Zhao J.J. SIK1 couples LKB1 to p53-dependent anoikis and suppresses metastasis. Sci Signal. 2009 2(80):ra35. PMC2752275.

Jia, S., Liu, Z., Zhang, S., Liu, P., Zhang, L., Lee, S.H., Zhang, J., Signoretti, S., Loda, M., Roberts, T.M. and
Zhao, J.J. Essential roles of PI(3)K-p110b in cell growth, metabolism and tumorigenesis. Nature, 2008; 454:776-9. PMC2750091



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