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Nutrient-Sensing Signaling Pathways Controlling Cancer and Diabetes

Research Summary

Reuben Shaw investigates mechanisms connecting cell metabolism to growth control. His lab utilizes biochemistry and genetic mouse models to study an ancient signaling pathway that is deregulated in both cancer and type 2 diabetes.

The central goal of our research is to elucidate mechanisms by which cells connect nutrient availability to cell growth and metabolism. Our work is focused on a highly conserved signal transduction pathway controlled by the AMP-activated protein kinase (AMPK) that, when deregulated, leads to cancer and metabolic disease. Activation of AMPK by the tumor-suppressor LKB1 under conditions of energy stress serves as a central switch that reprograms glucose and lipid metabolism and halts cell growth. LKB1, which encodes a serine/threonine kinase that is the cause of the inherited cancer disease Peutz-Jeghers syndrome, is also one of the most commonly mutated genes in lung cancer.

Using a combination of proteomic and bioinformatics approaches, we identified AMPK as a direct substrate of LKB1. AMPK, a highly conserved regulator of cell metabolism, 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 questions: Does AMPK have a role in tumor suppression? Conversely, does the LKB1 tumor suppressor have a role in metabolic control in critical tissues in mammals? We have found that both are true and that the phosphorylation of specific targets by AMPK mediates these wide effects on physiology.

One way that LKB1 and AMPK regulate tumorigenesis is through suppression 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. We have detailed the biochemical mechanism underpinning these events and have shown that activation of AMPK is a novel metabolic checkpoint in mammalian cells. Furthermore, these biochemical regulatory steps are conserved across all eukaryotes, which is extremely rare and suggests that this is one the most fundamental growth control pathways connecting nutrient status (glucose) to the growth control machinery (mTOR). This reinforces the idea that drugs that activate AMPK may serve as chemotherapeutics.

We also have been testing some of the therapeutic implications of our connection between LKB1, AMPK, and mTOR in mouse models of cancer. We performed a preclinical trial in a mouse model of Peutz-Jeghers syndrome, for which there is no current treatment other than surgical resection. Our previous studies demonstrated that LKB1-deficent tumors uniquely contain hyperactive mTOR. We have now tested whether LKB1-deficient tumors could be treated with the mTOR inhibitory drug rapamycin, which is currently in more than 40 ongoing phase II and phase III clinical trials in humans for various forms of cancer and has recently been approved and rapidly become the standard of care in the treatment of renal cell carcinoma. Treatment of LKB1 heterozygous mice with rapamycin led to a dramatic suppression of tumors. Further study revealed an mTOR- and HIF (hypoxia-inducible factor)-1α-dependent reprogramming of glucose metabolism and cell surface glucose transporters in these tumors, allowing them to be imaged noninvasively using flouro-deoxyglucose positron emission tomography (FDG-PET). These results suggest that in the future Peutz-Jeghers patients may be able to be treated by mTOR inhibitors. Moreover, even when surgical resection is still utilized, FDG-PET can be used to guide the surgery.

These findings have strong implications for the treatment and diagnosis of individuals with non-small-cell lung cancer (NSCLC), which is a major focus in my lab. NSCLC is the most common form of cancer worldwide due to its strong association with smoking, and LKB1 is one of the four most commonly mutated genes in NSCLC. We have created a genetic mouse model for sporadic lung cancer based on loss of LKB1 and activation of the K-ras oncogenes. In our genetic mouse model of NSCLC, LKB1 inactivation dramatically increases metastasis and tumor growth, as well as altering the spectrum of tumor types observed. We are using these mice to 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 anticancer therapeutics in the future. We are genetically defining the critical pathways regulated by LKB1 in this disease, as well as exploiting the activation of the LKB1-AMPK pathway by existing FDA-approved diabetes therapeutics as potential novel modalities for the treatment of NSCLC.

Given the connection between AMPK and diabetes, our lab is also devoting 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, the most-widely prescribed type-2 diabetes therapeutics in the world (taken by more than 100 million people daily), requires LKB1 signaling in the liver to exert its therapeutic benefit. In 2008, we collaborated with Ron Evans (HHMI, Salk Institute for Biological Studies) to demonstrate that AICAR, an AMPK-activating compound, is sufficient by itself to promote endurance, making it a unique exercise mimetic. We are now focused on identifying the key targets downstream of LKB1 in metabolic tissues, including liver and muscle, that mediate the beneficial and therapeutic effects of metformin and AICAR on metabolism.

Epidemiology studies have revealed a strong connection between metabolic disease, including obesity and type 2 diabetes, and an elevated risk for the development of certain forms of cancer. We are interested in which deregulation of the AMPK metabolic checkpoint contributes to this increased cancer risk. Conversely, both exercise and reduced calorie intake have been shown to reduce cancer risk in humans and rodents, and we are genetically examining the role of AMPK and mTOR signaling in this connection between exercise, nutrition, and cell proliferation.

Current efforts in our 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 ancient energy-sensing 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 connecting metabolism and cell growth will instruct us how to best exploit these endogenous mechanisms to combat specific forms of cancer and type 2 diabetes.

Grants from the National Institutes of Health, the American Cancer Society, the American Diabetes Association, the V Foundation for Cancer Research, the Leona and Harry Helmsley Charitable Trust, and the Adler Family Foundation provided partial support for these projects.

As of October 16, 2009

Scientist Profile

Early Career Scientist
Salk Institute for Biological Studies
Cancer Biology, Cell Biology