Dr. Nissim Hay
Distinguished Professor
- AAAS Fellow (2019)
- UIC University Scholar (2009-2012)
- PhD, The Weizmann Institute, Rehovot, Israel
Major Interests:
During the past two decades the major focus of this laboratory has been the role of the PI3K/Akt signaling pathway in the genesis of cancer and in cellular and organismal metabolism. The serine/threonine kinase Akt/PKB is perhaps the most frequently activated oncoprotein in human cancers. The hyperactivation of Akt in human cancers occurs largely through gain of function mutations in its upstream activator, the lipid kinase, PI3K, and through loss of function mutations in its upstream negative regulator the phospholipid phosphatase tumor suppressor PTEN that antagonizes PI3K.
This laboratory found that Akt is the major downstream effector of growth factor-mediated mammalian cell survival (Genes and Development 1997. 11: 701-713.). Subsequently, this laboratory revealed that Akt activity is required for mitochondrial integrity, at least in part, through mitochondrial hexokinases, which catalyze the first committed step in glucose metabolism (Genes and Development 2001.15: 1406-1418, Mol. Cell 2004. 16: 819-830). Studies in this laboratory showed for the first time that Akt is sufficient and required for growth factor mediated activation of the mammalian target of rapamycin, mTORC1 (Genes and Development 1998.12: 502-513). In subsequent studies we showed that the role of Akt in energy metabolism is important for the full activation of mTORC1, and that mTORC1 is the principal downstream effector of Akt required for cell proliferation and susceptibility to oncogenic transformation (Cancer Cell 2006.10: 269-280). Based on these observations pharmaceutical companies have been developing inhibitors of PI3K/Akt and mTORC1 for cancer therapy.
Over the years the laboratory has delineated the function of Akt at the cellular and organismal levels by targeting the Akt genes in the mouse. Single and compound Akt1, Akt2, and Akt3 knockout mice were characterized. Using Akt1 knockout mice, our laboratory provided a proof of concept that Akt activity could be reduced to a threshold level that inhibits cancer development in several mouse models of cancer, without eliciting severe physiological consequences.
Our laboratory provided evidence that the most evolutionarily conserved function of Akt in metabolism, particularly in energy metabolism, is coupled to its role in the genesis of cancer. We discovered the "Achilles' heel" of Akt. Akt activation in cancer cells increases the intracellular levels of reactive oxygen species (ROS), which are the byproducts of energy metabolism. While the elevation of intracellular ROS by Akt activation could potentiate tumorigenesis, it could also lead to the selective eradication of cancer cells displaying hyperactive Akt. Although Akt activation protects cancer cells from cell death induced by multiple stimuli, it does not protect from ROS-induced cell death. Thus, because Akt activation increases intracellular ROS, it sensitizes cells to killing by ROS. These observations prompted a therapeutic approach that selectively eradicates cancer cells displaying hyperactive Akt, while evading chemoresistance induced by Akt activation (Cancer Cell 2008. 14, 458-47).
In a landmark publication in 2012 in Nature, we showed that unlike the common view, AMPK activation can be pro-tumorigenic, and is required for cancer cell survival. When cells migrate to the lumen during solid tumor formation glucose consumption is inhibited, which is followed by energetic stress. Consequently, ROS levels are elevated because the cells cannot produce sufficient NADPH from the pentose phosphate pathway (PPP).
If NADPH level is not maintained, the cells undergo ROS-induced cell death. We showed that AMPK activation is required to maintain NADPH homeostasis under these conditions. We hypothesize that a similar energetic stress occurs when cells disseminate from the primary tumor site to distal sites during metastasis.
More recently we found that hexokinase 2 (HK2) is required for tumor initiation and maintenance in mouse models of breast and lung cancer. Furthermore, systemic deletion of HK2 inhibits tumor development in a mouse model for lung cancer without other adverse physiological consequences, providing a proof of concept that HK2 could be targeted for cancer therapy. This is the first demonstration that a major glycolytic enzyme can be systemically deleted in adult mice to inhibit cancer without adverse physiological consequences.
Our recent results showed that systemic Akt1 deletion in p53-/- mice eradicates thymic lymphoma in these mice and emulates p53 restoration. However, systemic deletion of Akt1 and Akt2 elicits rapid mortality, and unexpectedly hepatic deletion of Akt1 and Akt2 induces rapid hepatocellular carcinoma (HCC). These results have important implications for cancer therapy using pan-PI3K and pan-Akt inhibitors. The results also showed that unlike most other cancers Akt is not required for HCC development and its inhibition could promote HCC.
Ongoing projects in the laboratory include: further delineation of the roles of Akt in the genesis of cancer, metabolism, and lifespan; exploring new regulatory networks associated with Akt and its two most highly conserved downstream effectors, mTORC1 and FoxOs transcription factors; the role of mitochondrial hexokinase 2 in the genesis of cancer and implications for cancer therapy.
Selected Publications
Wang, Q., Yu, W.N., Chen, X., Peng, X.D., Jeon, S.M., Birnbaum, M.J., Guzman, G., and Hay, N. (2016). Spontaneous Hepatocellular Carcinoma after the Combined Deletion of Akt Isoforms. Cancer Cell 29, 523-535. (Preview in the same issue, Highlighted in Cancer Discovery).
Yu, W.N., Nogueira, V., Sobhakumari, A., Patra, K.C., Bhaskar, P.T., and Hay, N. (2015). Systemic Akt1 Deletion after Tumor Onset in p53 Mice Increases Lifespan and Regresses Thymic Lymphoma Emulating p53 Restoration. Cell Rep 12, 610-621.
Patra, K. C., Q. Wang, P. T. Bhaskar, L. Miller, Z. Wang, W. Wheaton, N. Chandel, M. Laakso, W. J. Muller, E. L. Allen, A. K. Jha, G. A. Smolen, M. F. Clasquin, R. B. Robey, and N. Hay. 2013. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell 24:213-28.(Selected as one of 12 best papers published in Cancer Cell in 2013, Highlighted in Cancer Discovery).
Jeon, S. M., Chandel, N. S., and Hay, N. (2012). AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485, 661-665. (News & Views, Faculty of 1000, Editor Choice Science Signaling, Higlighted in Cancer Discovery).
