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Reuben J. Shaw

 

Reuben J. Shaw

Reuben J. Shaw

Assistant Professor
Hearst Foundation Developmental Chair
Molecular and Cell Biology Laboratory

"When a normal cell runs low on energy, it won't divide, but in some cases, cancer cells can override the built-in shutoff. The same cellular brake helps cells and organisms adapt their glucose metabolism. I am particularly interested in understanding the molecular link between cancer and metabolism since it embodies a critical intervention point for future therapeutics."

People with Peutz-Jeghers syndrome, a rare inherited cancer syndrome caused by a mutation in the tumor suppressor LKB1, develop gastrointestinal polyps and are predisposed to colon cancer. Currently there is no treatment for Peutz- Jeghers; patients must undergo continual surgeries to remove the polyps and tumors as they arise. During earlier work, Shaw had discovered that LKB1 activates a metabolic master switch known as AMPK. If a cell runs on empty, LKB1 turns on AMPK, which puts a damper on cell growth and proliferation. When LKB1 is absent or disabled, cells facing starvation never get the message and continue to divide. AMPK operates via the mTOR pathway, short for "mammalian target of rapamycin." Rapamycin is a powerful immunosuppressant that binds and inactivates mTOR.

Since a loss of LKB1 results in a hyperactive mTOR signal, Shaw and his team hypothesized that rapamycin could be used to treat the tumors that arise as a result of Peutz-Jeghers. When administered to mice that had intestinal polyps because of an LKB1 mutation, rapamycin shrank their polyps and in most cases eliminated them altogether. The researchers then wondered whether they could visualize the drug's effectiveness using a technique called FDG-PET, which reveals the uptake of radioactively labeled glucose into cells. Normally, heart cells are the most ravenous consumers of glucose, but in patients with cancer, tumors light up. Most people assumed that polyps weren't far enough along on the road to malignancy to be visible on an FDG-PET scan, but Shaw's experiments revealed that the LKB1 mutation resulted in altered glucose metabolism in cells and tumors, allowing even benign LKB1 polyps to be clearly visible.

Their findings suggest that FDG-PET could be used to detect when polyps arise in people with Peutz-Jeghers syndrome, but also to monitor the therapeutic response to treatment. These findings also suggest that the subset of human lung cancers harboring alterations in the LKB1 gene may show altered glucose uptake, perhaps allowing for their early diagnosis and helping to dictate their therapeutic treatment.

Lab Photo

Left to right:
Front row: David Shackelford, Dana Gwinn, Annabelle Mery, Debbie Vasquez, Laurie Gerken, Reuben Shaw

Back row: Pierre-Damien Denechaud, Dan Egan, Maria Mihaylova, Rebecca Kohnz, Jonathan Goodwin

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Reuben J. Shaw

Faculty

Reuben J. Shaw

Reuben J. Shaw

Assistant Professor
Hearst Foundation Developmental Chair
Molecular and Cell Biology Laboratory

Reuben Shaw, assistant professor in the Molecular and Cell Biology Laboratory and the Dulbecco Laboratory for Cancer Research, studies signal transduction pathways that underlie the development of cancer as well as type 2 diabetes.

Our work centers around a human tumor suppressor named LKB1. LKB1 is mutationally inactivated in the familial cancer disease Peutz-Jegher Syndrome as well as in a 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 well known 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 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 the mTOR kinase, a conserved integrator of nutrient and growth factor signaling. We found that AMPK directly phosphorylates the TSC2 tumor suppressor and activates it to inhibit mTOR signaling. Consistent with this observation 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. We also generated a tissue-specific knockout of LKB1 in liver and also observed dramatic elevations of mTOR signaling in this context.

We chose to knockout LKB1 in liver as liver is known to be a tissue where AMPK activity is thought to be critical. Indeed, we found that loss of LKB1 led to a complete loss of AMPK activation and severe diabetes-like phenotypes in in these mice. We found that both gluconeogenic and lipogenic gene expression were upregulated in the livers of these mice, due in part to the loss of phosphorylation of a critical transcriptional coactivator termed TORC2 by AMPK and related kinases in the absence of LKB1. Finally we showed that metformin, one of the most widely prescribed type 2 diabetes therapeutics in the world, requires LKB1/AMPK signaling in the liver in order to exert its therapeutic benefit.

Future studies in our lab will focus on further elucidating these critical signaling pathways at this emerging interface between cancer and diabetes. We will employ a variety of biochemical, cell-biological, and genetic mouse models to dissect these biological processes. In addition, we will examine how existing diabetic therapeutics may be useful in the treatment of tumors with defined genetic lesions.

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