• Researcher Profile

    Charles W. Roberts, MD, PhD

     
    Charles W. Roberts, MD, PhD
     
    Director, Research Program in Solid Tumors

    Associate Professor of Pediatrics, Harvard Medical School

    Center/Program

    Pediatric Solid Tumors

    Office phone: 617-632-2072
    Fax: 617-582-8096
    Email: charles_roberts@dfci.harvard.edu
    Website: The Charles Roberts Lab

    Preferred contact method: email

    View Physician Profile
     
     

    Research Department

    Pediatric Oncology

    Interest

    Rhabdoid tumors

    Area of Research

    The Swi/Snf Complex: Chromatin and Cancer

    Dana-Farber Cancer Institute
    450 Brookline Avenue
    Mayer 657
    Boston, MA 02215

    Biography

    Dr. Roberts received his MD and PhD degrees in 1995 from Washington University, St. Louis, and then completed an internship and residency in pediatrics at Children's Hospital Boston. Following a fellowship in pediatric hematology-oncology at Children's Hospital Boston and DFCI, he joined the laboratory of Dr. Stuart Orkin for postdoctoral training. In 2003, he launched his own laboratory at DFCI, where his research focuses on the role of aberrant chromatin remodeling in cancer development.

    Recent Awards

    • Elected to membership in the American Society of Clinical Investigation, 2010
    • Elected to membership in the Society for Pediatric Research, 2007
    • Stephen E. Sallan Leadership Award, Dana-Farber Cancer Institute, 2005
    • American Association for Cancer Research Scholar-in-Training Award
      , 2003

    Research

    The Swi/Snf Complex: Chromatin and Cancer

    Our laboratory is interested in the role of dysfunctional chromatin remodeling in the genesis of cancer. The Swi/Snf complex, which utilizes ATP hydrolysis to remodel chromatin, has a potent role in tumor suppression. Unlike primary genetic mutations or covalent modifications such as methylation, the Swi/Snf complex does not leave a "mark" that can be readily assayed in cancer cells. Accumulating evidence has linked the Swi/Snf complex to both human cancer and other tumor suppressor pathways, indicating that the complex has diverse roles in growth regulation and tumor suppression.

    Indeed, we have demonstrated a key role for Snf5, a core member of this complex, in tumor suppression in a novel mouse model. Inactivating mutations in the SNF5 gene results in aggressive cancers in children and a familial cancer predisposition syndrome. We utilized homologous recombination to demonstrate that mice heterozygous for Snf5 are predisposed to develop tumors that are histologically identical to human malignant rhabdoid tumors. We also used novel mechanisms of conditional targeting to reveal that widespread induced inactivation of Snf5 leads to extremely rapid and aggressive cancer in 100% of mice, with a median latency of only 11 weeks.

    Previous kinetic studies of tumor formation have found that tumorigenesis typically requires four to six mutations, which is consistent with the relatively long latency of tumor formation observed in many animal models. What accounts for the extremely rapid onset of cancer following Snf5 inactivation? We hypothesize that Snf5 is a master regulator of gene expression via its effects on chromatin structure, and seek to identify the mechanisms by which perturbation of this ATPase chromatin remodeling complex leads to cancer formation. In fact, we recently found that Snf5 serves as a critical regulator of cell cycle checkpoints via the p16Ink4a/Rb/E2F pathway. Snf5 inactivation in primary cells leads to aberrant upregulation of E2F targets in primary cells and triggers p53-dependent apoptosis and growth arrest. Indeed, inactivation of p53 leads to dramatic acceleration of cancer onset in Snf5 conditional mice.

    Given the dramatic nature in which inactivation of a core subunit of the Swi/Snf complex, Snf5, leads to cancer formation, complete characterization of this complex will lead to insights into tumorigenesis and may further suggest novel therapeutic strategies. Therefore, we are using mouse models, as well as molecular, biological, and biochemical approaches to characterize this newly appreciated mechanism of tumor suppression.

    Select Publications

    • DelBove J, Kuwahara Y, Mora-Blanco EL, Godfrey V, Funkhouser WK, Fletcher CD, Van Dyke T, Roberts CW, Weissman BE. Inactivation of SNF5 cooperates with p53 loss to accelerate tumor formation in Snf5(+/-);p53(+/-) mice. Mol Carcinog. 2009 Dec;48(12):1139-48.
    • Wang X, Sansam CG, Thom CS, Metzger D, Evans JA, Nguyen PTL and Roberts CWM. Oncogenesis caused by loss of the SNF5 tumor suppressor is dependent upon activity of BRG1, the ATPase of the SWI/SNF chromatin remodeling complex. Cancer Research 2009; 69: 8094-8101.
    • Wilson BG, Wang X, Shen X, McKenna ES, Lemieux ME, Cho YJ, Koellhoffer EC, Pomeroy SL, Orkin SH, Roberts CWM. Epigenetic antagonism between Polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell 2010, Oct 19; 18(4): 316-28.
    • Jagani Z, Mora-Blanco EL, Sansam CG, McKenna ES, Wilson B, Chen D, Klekota J, Tamayo P, Nguyen PTL, Tolstorukov M, Park PJ, Cho YJ, Hsiao K, Buonamici S, Pomeroy SL, Mesirov JP, Ruffner H, Bouwmeester T, Luchansky S, Murtie J, Kelleher J, Warmuth M, Sellers WR, Roberts CWM*, and Dorsch M* (*Co-corresponding senior authors and contributed equally). Loss of the Tumor Suppressor Snf5 Leads to Aberrant Activation of the Hedgehog-Gli Pathway. Nat Med. 2010 Nov 14.

    Trainees

    • Sansam, Courtney, PhD
    • Wang, Xi, PhD
    • Wu, Jennifer, MD., Ph.D
    • Wilson, Boris, Ph.D
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