Welcome to the Shaw Laboratory at the Salk Institute for Biological Studies. The Salk Institute is situated on the cliffs above the Pacific Ocean in La Jolla, CA and offers views of the ocean from the courtyard. The Shaw Lab is part of the Molecular and Cell Biology Laboratory (MCBL), a group consisting of outstanding researchers in the fields of Cancer, Molecular and Cell Biology, and Aging. We are working to understand the links between metabolism and cancer in an effort to add to the growing body of knowledge with respect to potential avenues or targets for therapeutics.

Our work centers around a human tumor suppressor named LKB1.  LKB1 is mutationally inactivated in the familial cancer disease Peutz-Jeghers Syndrome as well as in large percentage of sporadic lung adenocarcinomas. Interestingly, LKB1 encodes a threonine kinase that serves to activate a number of downstream kinases, including the AMP-activated protein kinase (AMPK), which is a critical regulator of metabolism, and the par-1/MARK family of kinases that regulate cell polarity.

Using a combination of proteomic and bioinformatics approaches, we identified AMPK as a direct substrate of LKB1. AMPK is a highly conserved regulator of cell metabolism that is activated under conditions of energy stress. We propose that the LKB1-dependent activation of AMPK in response to these stress stimuli may act as a low energy or metabolic checkpoint in the cell.  This unexpected connection between a well-known regulator of cellular metabolism and a tumor suppressor gene led to two immediate questions: Does AMPK have a role in tumor suppression and conversely, does the LKB1 tumor suppressor have a role in metabolic control in critical tissues in mammals? We have found that indeed both are true and that through the phosphorylation of specific targets by AMPK, these wide effects on physiology are regulated.

One way that LKB1 and AMPK regulate tumorigenesis is through regulation of mTOR (mammalian target of rapamycin), a conserved integrator of nutrient and growth factor signaling. We found that AMPK directly phosphorylates the TSC2 tumor suppressor and the key mTOR binding partner raptor.   Collectively these events inhibit mTOR and cause cell cycle arrest.   This reinforces the idea that drugs which activate AMPK may serve as chemotherapeutics.

Consistent with these observations from cell culture, tumors lacking LKB1 were found to contain elevated levels of mTOR compared to surrounding epithelium. These findings culminated in the observation that three different human hamartoma syndromes, involving loss of TSC1/2, PTEN, and LKB1, all share a common biochemical underpinning: hyperactivation of mTOR signaling.  Based on these findings, we suggested that these tumor types may be effectively treated with mTOR inhibitors such as rapamycin.  In preclinical trials in a mouse model of Peutz-Jeghers syndrome, we have found that rapamycin very effectively suppresses tumor formation.  Further study of this model revealed an mTOR- and HIF1a-dependent reprogramming of glucose metabolism in these tumors, making them now visible by FDG-PET.  These results indicate that in the future Peutz-Jeghers patients may be able to be treated by mTOR inhibitors and even when surgical resection is utilized, FDG-PET can be used to guide the surgery. 

We also have a major research effort underway studying the role of LKB1 in the suppression of non-small cell lung carcinoma (NSCLC), the most common form of human lung cancer, in which LKB1 is one of the most frequently mutated genes.  In our genetic mouse model of non-small cell lung cancer, LKB1 inactivation dramatically increases metastasis and tumor growth, as well as altering the spectrum of tumor types observed.  We are currently using these mice to further explore the use of therapeutics that target the tumor cell’s glucose metabolism or energy state as a means to kill tumor cells with specific genetic mutations.  We believe that individualized medicine aimed at each tumor’s unique Achilles heel will be the mechanism for most anti-cancer therapeutics in the future.

Finally, given the connection between AMPK and diabetes, our lab devotes significant effort to studying type 2 diabetes.  We previously demonstrated that inactivation of LKB1 in murine liver leads to severe diabetes-like phenotypes in these mice.  Moreover, we showed that metformin (Glucophage^TM), the most-widely prescribed type 2 diabetes therapeutic in the world, which over 100 million people take daily, requires LKB1 signaling in the liver in order to exert its therapeutic benefit.  During a collaborative effort in 2008, we assisted the laboratory of Ron Evans here at the Salk in demonstrating that an AMPK activating compound named AICAR was sufficient by itself to promote endurance, making it a unique exercise mimetic.  We are currently focused on identifying the key targets downstream of LKB1 in metabolic tissues including liver and muscle that mediate the beneficial effects of metformin and AICAR on metabolism. 

Current efforts in the laboratory are aimed at further identifying the key components of this signaling pathway that suppress tumorigenesis and metabolic disease, as well as decoding the circuits linking fundamental cell biological processes to physiology. We employ a variety of biochemical, cell-biological, and genetic mouse models to dissect these biological processes.   The discovery of this highly LKB1 conserved pathway has already led to fundamental insights into the mechanisms through which all eukaryotic organisms couple their growth to nutrient conditions and metabolism.  A deeper understanding of the key components of this pathway will not only lead to future therapeutic targets for cancer and diabetes, but will reveal the minimal number of steps required to suppress tumorigenesis and reprogram metabolism.