BBS Faculty Member - Charles Roberts

Charles Roberts

Department of Biological Chemistry and Molecular Pharmacology

Dana-Farber Cancer Institute
Mayer Building, Room 657
44 Binney Street
Boston, MA 02115
Tel: 617-632-6497
Fax: 617-582-8096
Email: charles_roberts@dfci.harvard.edu
Visit my lab page here.



My laboratory is interested in the role of dysfunctional chromatin remodeling in the genesis of cancer. It is increasingly clear that epigenetic modifications play a critical role in the development of cancer. For example, silencing of tumor suppressor genes via promoter methylation is a widespread feature of cancer. Similarly, complexes that covalently modify chromatin, such as the histone acetylase and deacetylase complexes, are involved in oncogenesis. The Swi/Snf complex, which utilizes ATP hydrolysis to remodel chromatin, is emerging as a major tumor suppressor complex frequently mutated in a variety of cancer types including pediatric, endometrial, kidney and lung cancers. We have recently 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 result 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 utilized novel mechanisms of conditional targeting to reveal that widespread induced inactivation of Snf5 leads to extremely rapid and aggressive cancer with 100% of mice developing lymphomas and rhabdoid tumors 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. Given the dramatic nature in which inactivation of a core subunit of the Swi/Snf complex, Snf5, leads to cancer formation, characterization of this complex including its roles in chromatin remodeling and mechanisms of target gene regulation will lead to new insights into tumorigenesis and may further suggest novel therapeutic strategies. Thus, we are using mouse modeling, molecular biological, and biochemical approaches to characterize this newly appreciated and potent mechanism of tumor suppression.





























Last Update: 8/22/2013



Publications

For a complete listing of publications click here.

 


 

Lee RS, Stewart C, Carter SL, Ambrogio L, Cibulskis K, Sougnez C, Lawrence MS, Auclair D, Mora J, Golub TR, Biegel JA, Getz G, Roberts CWM. A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. J Clin Invest. 2012;122(8):2983–2988.

Wilson BG and
Roberts CWM. SWI/SNF nucleosome remodelers and cancer. Nature Reviews Cancer 2011; 11:481-92.

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. Nature Medicine 2010; 16: 1374-6.

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.

McKenna ES, Sansam CG, Cho YJ, Greulich H, Evans JA, Thom CS, Moreau LA, Biegel JA, Pomeroy SL and
Roberts CWM: Loss of the epigenetic tumor suppressor SNF5 leads to cancer without genomic instability. Molecular and Cellular Biology 2008, 28: 6223-33.

Tamayo P, Scanfeld D, Ebert BL, Gillette MA,
Roberts CWM, and Mesirov JP: Metagene Projection: a cross platform, cross species characterization of global transcriptional states. Proceedings of the National Academy of Sciences, USA 2007; 104: 5959-64.

Isakoff MS, Sansam CG, Tamayo P, Subramanian A, Evans JA, Fillmore CM, Wang X, Biegel JA, Pomeroy SL, Mesirov JP and
Roberts CWM: Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation. Proceedings of the National Academy of Sciences, USA 2005; 102: 17745-17750.



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