Our laboratory is interested in deciphering the molecular mechanisms of metabolic signaling in cancer, with special emphasis on melanoma, and translating these basic research findings into potential personalized targeted therapies. The focus of our current research is on the LKB1-AMPK signaling pathway, which couples energy metabolism to cell growth, proliferation and survival. AMPK (AMP-activated protein kinase) is a Ser/Thr protein kinase thatserves as a cellular energy sensor. The activity of AMPK is regulated by the AMP/ATP ratio and by upstream activating kinases, including the tumor suppressor LKB1. Metformin, one of the most prescribed drugs for treating type II diabetes, has been shown to target the LKB1-AMPK pathway and is currently being evaluated for the treatment of cancer in clinical trials. Understanding the complex LKB1-AMPK signaling circuitries underlying tumorigenesis will contribute to the development of effective therapeutic strategies.
Our current research directions include:
1) Identification of novel substrates of AMPK and characterization of their roles in cancer biology. We are using a combination of bioinformatics, proteomics and metabolomics approaches to uncover critical AMPK substrates relevant to cancer biology, especially those involved in cancer cell metabolism and EMT (Epithelial Mesenchymal Transition).
2) Down-regulation of LKB1 and AMPK in Cancer. The LKB1-AMPK pathway serves as an "energy brake" to suppress cell growth and proliferation under energy stress conditions. Cancer cells need to inactivate this pathway in order to gain a growth advantage over normal cells. We are studying various mechanisms by which the LKB1-AMPK "energy brake" is "overridden" in cancer.
3) Cross-talk between LKB1-AMPK and RAF-MEK-ERK signaling pathways. RAF signaling pathway is one of the other most important signaling pathways in cancer. We have recently discovered that this pathway is tightly linked to the LKB1-AMPK pathway. Currently we are continuing to investigate the biochemical mechanism by which these two pathways interact and regulate each other's functions. Moreover, we are assessing the therapeuticpotential of combining drugs targeting both of these pathways (metformin and RAF/MEK inhibitors) in melanoma treatment using various preclinical models, such as xenograft and genetically engineered mouse models.