Section: Research

Postdoctoral Position Available

David Guertin, Ph.D.

Academic Role: Assistant Professor

Faculty Appointment(s) In:
   Program in Molecular Medicine

Joint Faculty In:
   Clinical and Translational Sciences
   Diabetes
   Endocrinology
   Interdisciplinary Graduate Program

    

Signal Transduction in Development and Cancer

How do cells decide whether to grow, divide, die, migrate, differentiate, or remain quiescent in response to signals in their extra-cellular environment? This is a fundamental question in cell biology and is at the root of many diseases, yet we understand little about how these choices are made. Normally, cells sense the presence of hormones, growth factors, mitogens, nutrients, cytokines, and other factors, and then through signal transduction pathways, integrate this information into a biological response. In cancer, mutations uncouple the activation of these signaling pathways from their normal regulatory mechanisms, resulting in cellular transformation.  I would like to understand how signaling networks integrate information to control development and tissue regeneration and how a defect in this signaling circuitry drives cancer.

The work in my laboratory focuses on signal transduction pathways that control cell, organ, and organism growth.  We are specifically interested in the mTOR-signaling pathway, which is an essential regulator of growth in many eukaryotic species.  At the core of this pathway is a highly conserved protein kinase called mTOR (mammalian target of rapamycin).  mTOR integrates growth regulatory signals from many diverse inputs including nutrients and growth factors, and in response, phosphorylates a wide array of effectors that regulate processes important for growth, such as protein synthesis, cell division, apoptosis, and autophagy.  An important step in understanding the biology of mTOR signaling was the discovery that mTOR does not function alone in cells, but as part of at least two distinct multi-protein complexes, called mTORC1 and mTORC2 (Figure 1).  Each mTOR complex contains different mTOR-interacting proteins, which direct mTOR kinase activity towards unique substrates.  Understanding the roles of each mTOR complex in regulating cell, organ, and organism growth is the long-term goal of my lab.   

Figure 1.  The mTOR kinase forms at least two distinct complexes called mTORC1 and mTORC2.

Biochemical studies into the mechanism of how mTOR controls cell growth revealed that mTOR exists in at least two distinct complexes called mTORC1 and mTORC2.   In cells, the mTOR complexes serve as signal integration centers because their activity is influence by inputs from diverse sources.  Each complex contains numerous subunits, some common to both complexes, and others that are unique to either mTORC1 or mTORC2.  The unique subunits direct mTOR kinase activity towards specific substrates, including the 4E-BP1 protein, a regulator of protein synthesis, and the AGC-family kinases S6K, AKT, and SGK, which control many cellular processes including cell growth, proliferation, apoptosis, and ion transport.

Targeting mTOR in cancer

It is now widely accepted that aberrant activation of mTOR signaling is a characteristic of most human cancers and intense efforts are underway to develop inhibitors of mTOR for use in oncology.  One class of mTOR inhibitors is based on the chemical structure of rapamycin, a natural product of the soil bacterium Streptomyces hygroscopius and the molecule from which mTOR derives its name.  Rapamycin shows promise against a number of cancers, but in general, it has not lived up to expectations in the clinic and success with the drug is unpredictable.  This is likely due to the fact that rapamcyin binds mTOR outside of the catalytic site and only partially inhibits mTOR activity.  However, second generation mTOR inhibitors targeting the kinase domain are becoming available marking an exciting new phase in mTOR-based therapy.  To facilitate the development of these inhibitors, we are using mouse genetics, mouse tumor models, and human cancer cells to define the roles of mTOR in cancer and the potential value of mTOR inhibitors as therapeutics.

Catalytic inhibitors of mTOR target both mTORC1 and mTORC2.  However, the efficacy of this class of inhibitors is still unclear.   We wondered if there is therapeutic value in developing mTOR complex-specific inhibitors that would only target either mTORC1 or mTORC2.  Using a mouse model of prostate cancer, we addressed this question for mTORC2.  We found that deleting an essential regulatory subunit of mTORC2 in the prostate epithelium of mice prevented the onset of prostate cancer driven by loss of the PTEN tumor suppressor (Figure 2).  Remarkably, inhibiting mTORC2 in otherwise normal prostate cells had no deleterious effects!  An inhibitor that compromises a cancer cell but not a normal cell would be a valuable anticancer therapeutic.  Our finding suggests that mTORC2-specific inhibitors may have substantial clinical value and we are exploring this possibility using a combination of mouse genetics, mammalian cell culture, and pharmacological studies.    

Figure 2.  mTORC2 is required for prostate cancer induced by loss of the PTEN tumor suppressor. 

(A-C)  H&E stains of the prostate epithelium.  (A) Section of prostate epithelium from a wild-type mouse.  (B) Deletion of the PTEN tumor suppressor in the prostate epithelium leads to prostate cancer with short latency.  (C) Inactivation of mTORC2 blocks prostate cancer formation induced by PTEN loss.  (D-F) Sections are labeled with a phospho-specific antibody to the mTORC2 substrate Akt.  (D) Akt phosphorylation is low in a normal prostate epithelium.  (E) Akt phosphoryaltion is dramatically elevated in prostate epithelial cells when PTEN is deleted.  (F) Inactivation of mTORC2 blocks the hyperphosphorylation of Akt induced by PTEN loss.     

mTOR signaling in development and tissue regeneration

During development or when adult tissue is being repaired or regenerated, extrinsic and intrinsic factors tightly regulate signaling pathways in stem and progenitor cells.  Growth factor signaling in particular has long been known to regulate stem cell fate decisions.  However, the role of nutrient sensing pathways in stem cell control is unclear.  Stem cells may be valuable therapeutically to repair diseased or injured tissue, and “cancer stem cells” may be the critical targets in some cancer therapies. Thus, understanding the molecular control of stem cell function has broad implications.  

We are particularly interested in muscle stem cells because muscle is a highly nutrient sensitive and metabolically important tissue, and regenerating damaged muscle requires the activation, proliferation, migration, and differentiation of stem cells.  Importantly, muscle degeneration is problematic in diseases like muscular dystrophy and it is hopeful that stem cell therapy will someday offer an effective treatment.  Muscle degeneration is also associated with cancer and aging.  Our preliminary studies suggest that mTOR regulates the self-renewal and differentiation of purified muscle stem cells.   As is our custom, we are taking a multidisciplinary approach using in vivo mouse models, purified muscle stem cells, and pharmacological agents to define the individual roles of mTORC1 and mTORC2 in muscle stem cells and in muscle regeneration.

Office: Bio2 211
Phone: 68064
E-mail: David.Guertin@umassmed.edu

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Postdoctoral Position Available  A postdoctoral position is available to study in this laboratory. Contact Dr. Guertin for additional details.