Charles W.M. Roberts

Departmentof 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

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, has a potent role in the genesis of cancer. 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 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, complete characterization of this complex will lead to 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 mechanism of tumor suppression.

References:

• 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, In Press.

• 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.