The focus of the Chan laboratory is to understand the genomic basis of tumor development and progression. We utilize both large-scale genomic analyses and functional dissection to elucidate the drivers of oncogenesis.
Our research focuses on the following areas of investigation.
First, we are interested in identifying and characterizing novel, multisite tumor suppressor genes. We currently focus these efforts on glioblastoma (GBM), colon cancer, and breast cancer. We have developed large-scale genome-wide strategies that enable the efficient identification of genes that are mutated, deleted, or epigenetically silenced in cancer. We utilize these genome-wide genetic and epigenetic approaches to identify and characterize novel cancer genes that are important for the initiation and progression of cancer. Using these approaches, we have identified a collection of multisite tumor suppressors that may be fundamentally important for the development of many cancers.
For example, our lab has recently identified the E3 ligase PARK2 as a driver of loss in the frequently deleted region 6q25-27. We identified mutations of PARK2 in multiple human cancers and showed that these mutations disrupt the ability of PARK2 to regulate cyclin E and maintain genetic stability. Intriguingly, PARK2 mutations are also the most frequent cause of early onset Parkinson's disease. Our results indicate that mutation of PARK2 in the absence of an oncogenic context (i.e., in neurons) may lead to neurodegeneration but mutation of PARK2 in replication-competent cells may cooperate with other genetic lesions to initiate tumorigenesis.
Mutations of PARK2 in cancer and Parkinson’s disease
Current efforts focus on dissecting the molecular function of PARK2 in cancer using cell biological and animal models. Significant efforts are also under way to define the function of other tumor suppressors we have identified, including the PTPRD tyrosine phosphatase, and to identify other driver lesions in currently ill-defined regions of the cancer genome.
Second, our lab studies the molecular mechanisms underlying metastasis. It is increasingly clear that systematic epigenomic aberrations are fundamentally important for the development of metastatic lesions. We have recently shown, for the first time, that systematic derangement of the breast cancer methylome dictates the gene-expression changes underlying the metastasis transcriptome. Current efforts here focus on defining the metastasis epigenome and utilizing our findings to develop better prognostic and therapeutic options for patients.
Veeriah S, Taylor BS, Meng S, Fang F, Yilmaz E, Vivanco I, Janakiraman M, Schultz N, Hanrahan AJ, Pao W, Ladanyi M, Sander C, Heguy A, Holland EC, Paty PB, Mischel PS, Liau L, Cloughesy TF, Mellinghoff IK, Solit DB, Chan TA. Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies. Nat Genet. 2010 Jan;42(1):77-82. doi: 10.1038/ng.491. Epub 2009 Nov 29.
Fang F, Turcan S, Rimner A, Kaufman A, Giri D, Morris LG, Shen R, Seshan V, Mo Q, Heguy A, Baylin SB, Ahuja N, Viale A, Massague J, Norton L, Vahdat LT, Moynahan ME, Chan TA. Breast cancer methylomes establish an epigenomic foundation for metastasis. Sci Transl Med. 2011 Mar 23;3(75):75ra25. doi: 10.1126/scitranslmed.3001875.
Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E, Campos C, Fabius AW, Lu C, Ward PS, Thompson CB, Kaufman A, Guryanova O, Levine R, Heguy A, Viale A, Morris LG, Huse JT, Mellinghoff IK, Chan TA. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012 Feb 15;483(7390):479-83. doi: 10.1038/nature10866.
Morris LG, Kaufman AM, Gong Y, Ramaswami D, Walsh LA, Turcan Ş, Eng S, Kannan K, Zou Y, Peng L, Banuchi VE, Paty P, Zeng Z, Vakiani E, Solit D, Singh B, Ganly I, Liau L, Cloughesy TC, Mischel PS, Mellinghoff IK, Chan TA. Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation. Nat Genet. 2013 Mar;45(3):253-61. doi: 10.1038/ng.2538. Epub 2013 Jan 27. [PMID:23354438]
Ho AS, Kannan K, Roy DM, Morris LGT, Ganly I, Katabi N, Ramaswami D, Walsh LA, Eng, Stephanie, Huse JT, Zhang J, Dolgalev I, Huberman K, Heguy A, Viale A, Drobnjak M, Leversha MA, Rice CE, Singh B, Iyer NG, Leemans CR, Bloemena E, Ferris RL, Seethala RR, Gross BE, Liang Y, Sinha R, Peng L, Raphael BJ, Turcan S, Gong Y, Schultz N, Kim S, Chiosea S, Shah JP, Sander C, Lee W, Chan TA* (*corresponding author). The mutational landscape of adenoid cystic carcinoma. Nat Genet. 2013 May 19;45(7):791-8. doi: 10.1038/ng.2643. Epub 2013 May 19.
Era of Hope Scholar, Department of Defense (2012)
Frederick R. Adler Chair for Junior Faculty, Memorial Sloan Kettering Cancer Center (2012)
Member, American Society of Clinical Investigation (2012)
Distinguished Scientist Award, Sontag Foundation (2010)
Han-Mo Koo Memorial Lectureship Award, Van Andel Institute (2010)
Clinical Scientist Development Award, Doris Duke Charitable Foundation (2009)
Scholar Award, Flight Attendant Medical Research Institute (2008)
Louis V. Gerstner Investigator Award, Memorial Sloan Kettering Cancer Center (2008)