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.



The Roberts laboratory studies the SWI/SNF (BAF) chromatin remodeling/tumor suppressor complex. We first began studying the complex over a decade ago when it was shown that the SNF5/SMARCB1/INI1/BAF47 subunit was specifically mutated in nearly all cases of malignant rhabdoid tumor, a highly aggressive and lethal cancer of early childhood. Recent data now demonstrate that at least eight separate subunits of this complex are recurrently and specifically mutated in a wide variety of cancers, collectively occurring in 20% of all human cancers. Consequently, the SWI/SNF complex is the most frequently mutated chromatin regulatory complex with a mutation frequency that exceeds many classical tumor suppressors and oncogenes. The SWI/SNF complex, which utilizes ATP hydrolysis to remodel chromatin, has a role in epigenetic regulation via nucleosome remodeling based control of lineage-specific transcription. We have demonstrated key roles for SNF5, a core member of this complex, in tumor suppression using genetically engineered mouse models. We hypothesize that the SWI/SNF complex 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 SNF5 drives cancer formation, characterization of this complex will lead to insights into the mechanisms of tumorigenesis. Thus, we are using mouse modeling combined with molecular, cellular and biochemical approaches to characterize this newly appreciated mechanism of tumor suppression and to identify novel therapeutic targets. Our work principally focuses upon basic and translational research, but our work has now led to an open clinical trial as well.



Last Update: 6/18/2014



Publications

For a complete listing of publications click here.

 


 

Helming KC, Wang X, Wilson BG, Vazquez F, Haswell JR, Manchester HE, Kim Y, Kryukov, Ghandi M, Aguirre AJ, Jagani Z, Wang Z, Garraway LA, Hahn WC, and Roberts CWM. ARID1B is a specific vulnerability in ARID1A-mutant cancers. Nature Medicine 2014; 20(3): 251-4.

Wilson BG, Helming KC, Wang X, Kim Y, Vazquez F, Jagani Z, Hahn WC, and
Roberts CWM. Residual complexes containing SMARCA2 (BRM) underlie the oncogenic drive of SMARCA4 (BRG1) mutation. Molecular and Cellular Biology 2014; 34(6):1136-44

Tolstorukov MY, Sansam CG, Lu P, Koellhoffer EC, Helming KC, Alver BH, Tillman EJ, Evans JA, Wilson BG, Park PJ and
Roberts CWM. Swi/Snf chromatin remodeling/tumor suppressor complex establishes nucleosome occupancy at target promoters. Proceedings of the National Academy of Sciences 2013; 110:10165-70.


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.



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