Charles M. Roberts, MD, PhD
|Hospital Title||Principal Investigator|
|Academic Title||Associate Professor|
|Charles M. Roberts|
44 Binney Street
Boston, MA 02115
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. The Swi/Snf complex, which utilizes ATP hydrolysis to remodel chromatin, has a potent role in the genesis of cancer. At least six SWI/SNF subuntis have recently been found to be recurrently and frequently mutated in a variety of human cancers, including in highly pediatric cancers called malignant rhabdoid tumors as well as in substantial subsets of lung, breast, prostate, colorectal, ovarian, pancreas, stomach, liver, kidney, and bladder cancers. 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, wWe have recently demonstrated the functional significance of these mutations by generating mice carrying conditional mutations in a key role for Snf5, a core member of this complex, and finding that 100% of these mice develop cancer, with a median onset of only 11 weeks. This rate is remarkably rapid for the inactivation of a single gene, and is indeed twice as fast as P53 deficient mice develop cancer. 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 are now focused upon elucidating the mechanism by which mutation of SWI/SNF subunits drives cancer growth with a goal of identifying new ways to therapeutically intervene in these cancers. 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 Snf5, leads to cancer formation, cComplete characterization of this complex will lead to insights into tumorigenesis and may should identify 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.
Lee RS, Stewart C, Carter SL, Ambrogio L, Cibulskis K, Sougne C, Lawrence MS, Auclair D, Mora J, Golub TR, Biegel JA, Getz G, and Roberts CWM. A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. Journal of Clinical Investigation 2012, In Press.
Wang X, Werneck MBF, Wilson BG, Kim H-J, Kluk MJ, Thom CS, Wischhusen JW, Evans JA, Jesneck JL, Nguyen P, Sansam CG, Cantor H, Roberts CWM. T cell receptor dependent transformation of mature memory phenotype T cells in mice. Journal of Clinical Investigation 2011; 121: 3834-3845.
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*. Loss of the Tumor Suppressor Snf5 Leads to Aberrant Activation of the Hedgehog-Gli Pathway. Nature Medicine 2010; 16: 1374-6. *Co-corresponding senior authors and contributed equally.
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.
Wang X, Sansam CG, Thom CS, Metzger D, Evans JA, Nguyen PT, Roberts CW. Oncogenesis caused by loss of the SNF5 tumor suppressor is dependent on activity of BRG1, the ATPase of the SWI/SNF chromatin remodeling complex.Cancer Res 2009 Oct 15;69(20):8094-101 19789351
McKenna ES,Sansam CG,Cho YJ,Greulich H,Evans JA,Thom CS,Moreau LA,Biegel JA,Pomeroy SL,Roberts CW. Loss of the epigenetic tumor suppressor SNF5 leads to cancer without genomic instability.Mol Cell Biol 2008 Oct;28(20):6223-33. 17389406
Sansam CG, Roberts CW. Epigenetics and cancer: altered chromatin remodeling via Snf5 loss leads to aberrant cell cycle regulation.Cell Cycle 2006 Mar;5(6):621-4. 16582616
Isakoff MS, Sansam CG, Tamayo P, Subramanian A, Evans JA, Fillmore CM, Wang X, Biegel JA, Pomeroy SL, Mesirov JP, Roberts CW. Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation. Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17745-50. 16301525
Roberts CW, Orkin SH. The SWI/SNF complex--chromatin and cancer.Nat Rev Cancer 2004 Feb;4(2):133-42. 14964309
Roberts CW, Leroux MM, Fleming MD, Orkin SH. Highly penetrant, rapid tumorigenesis through conditional inversion of the tumor suppressor gene Snf5.Cancer Cell 2002 Nov;2(5):415-25. 12450796
- Roberts CW, Galusha SA, McMenamin ME, Fletcher CD, Orkin SH. Haploinsufficiency of Snf5 (integrase interactor 1) predisposes to malignant rhabdoid tumors in mice.Proc Natl Acad Sci U S A 2000 Dec 5;97(25):13796-800. 11095756