Department of
Biological Chemistry & Molecular Pharmacology

Jean Zhao

Dana Farber Cancer Institute
Smith Building, Room 936B
450 Brookline Ave.
Boston, MA 02215

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. For example, PIK3CA plays essential roles in cellular signaling in response to various growth factors, while PIK3CB is important in mediating GPCR signaling. PIK3CA is critical in regulating hepatic and hypothalamic insulin action, glucose homeostasis and energy expenditure. We also made the surprising and important discovery that it is PIK3CB, not PIK3CA, that drives tumor formation in PTEN null prostate tumors. This work provided the foundation for a new field of targeting PI3K isoforms in cancer.

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 oncogenes. 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.

In summary, 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.

  • Chittenden TW, Pak J, Rubio R, Cheng H, Holton K, Prendergast N, Glinskii V, Cai Y, Culhane A, Bentink S, Schwede M, Mar JC, Howe EA, Aryee M, Sultana R, Lanahan AA, Taylor JM, Holmes C, Hahn WC, Zhao JJ, Iglehart JD, Quackenbush J.Therapeutic implication
  • Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA, Emery CM, Stransky N, Cogdill AP, Barretina J, Caponigro G, Hieronymus H, Murray RR, Salehi-Ashtiani K, Hill DE, Vidal M, Zhao JJ, Yang X, Alkan O, Kim S, Harris JL, Wilson CJ, Myer VE,
  • Xu Y, Hill JW, Fukuda M, Gautron L, Sohn JW, Kim KW, Lee CE, Choi MJ, Lauzon DA, Dhillon H, Lowell BB, Zigman JM, Zhao JJ, Elmquist JK.PI3K signaling in the ventromedial hypothalamic nucleus is required for normal energy homeostasis.Cell Metab. 2010 Jul 4
  • Sopasakis VR, Liu P, Suzuki R, Kondo T, Winnay J, Tran TT, Asano T, Smyth G, Sajan MP, Farese RV, Kahn CR, Zhao JJ.Specific roles of the p110alpha isoform of phosphatidylinsositol 3-kinase in hepatic insulin signaling and metabolic regulation.Cell Metab.
  • Hill JW, Xu Y, Preitner F, Fukuda M, Cho YR, Luo J, Balthasar N, Coppari R, Cantley LC, Kahn BB, Zhao JJ, Elmquist JK.Phosphatidyl Inositol 3-Kinase Signaling in Hypothalamic Proopiomelanocortin Neurons Contributes to the Regulation of Glucose Homeostasis