I direct a Laboratory of Cancer Molecular Genetics and Epigenetics at the Sidney Kimmel Comprehensive Cancer Center (SKCCC), and am also the Director of the SKCCC Next Generation Sequencing Center. My research is focused on understanding the complex interplay between genetic and epigenetic alterations in carcinogenesis and disease progression, and to exploit this understanding in developing novel biomarkers for diagnosis and risk stratification as well as in identifying targets for therapeutic intervention. Along this theme, my laboratory has charted three broad categories of investigation:
1) Understanding the complex interplay of genetic and epigenetic processes in establishing and maintaining the neoplastic phenotype
It is now clear that cancer initiation and progression occurs through the acquisition of somatic genome alterations at both the genetic and epigenetic levels. Interestingly, genetic and epigenetic processes are often seen to cooperate to establish and maintain the neoplastic phenotype in cancer cells. While much recent effort has focused on understanding the inherited and somatic genome alterations occurring in human cancer, it is becoming clear that this is an incomplete picture without the simultaneous and integrated understanding of epigenetic alterations. A major limitation has been the lack of robust, cost-effective, quantitative and integrative technologies for the assessment of epigenetic processes alongside the genetic processes.
My lab has developed and optimized a novel suite of technologies that harness the power of microarrays and next generation sequencing for integrated, cost-effective, and quantitative measurement of genetic and epigenetic alterations. We are currently applying these technologies to understand the cooperation of genetic alterations, such as mutations, deletions, amplifications, and rearrangements, with epigenetic alterations, such as DNA methylation changes, in carcinogenesis and disease progression. These analyses have helped identify novel tumor suppressor and metastasis suppressor genes that we are currently functionally characterizing using gain- and loss-of-function experiments. In addition to providing insights into cancer biology, these analyses have helped to nominate several DNA based biomarkers for cancer detection, risk stratification, and prediction of treatment response.
2) Targeting epigenetic alterations for cancer therapy
Epigenetic gene silencing ubiquitously accompanies the development of cancer; reactivation of silenced genes has emerged as a rational treatment strategy. Unfortunately, epigenetic drugs have only had limited success as single agent therapies for human cancers including prostate cancer, and there has been a somewhat haphazard approach to empirically identify drug combinations that may synergize with epigenetic drugs. In a collaboration with Bill Nelson’s laboratory, we have developed a novel, rational, approach to identification of effective drug combinations with epigenetic drugs that can induce synthetic lethality of cancer cells.
3) Role of genome organization and TOP2B in androgen signaling, transcription, and genomic instability
Androgen receptor (AR) signaling is critical to the pathogenesis of prostate cancer and AR is a critical therapeutic target in prostate cancer. Androgen receptor (AR) signaling involves a complex and coordinated series of events that include binding of androgen hormones by the receptor, binding of the liganded receptor complex to diverse sites on the genome, and dynamic reorganization of the genome to facilitate efficient target gene expression. My lab has recently shown that topoisomerase II beta (TOP2B) is co-recruited with AR to target sites where it often carries out its catalytic cleavage, and that its recruitment and catalytic activity are required for efficient AR target gene expression. We have also shown that androgen stimulation promotes co-recruitment of AR and TOP2B to sites of recurrent rearrangement breakpoints in prostate cancer, triggering recombinogenic TOP2B-mediated double strand breaks. These data suggest that androgen signaling and associated intrinsic transcriptional programs require TOP2B, and also that such processes can be corrupted, leading to TOP2B-mediated genomic breaks that may ultimately nucleate genomic rearrangements in prostate and other cancers. TOP2B mediated DNA breaks are also evident in other induced transcriptional programs, including those governed by ER, RAR, insulin signaling, and others.
Based on these data, we hypothesize that TOP2B may be involved in relieving topological constraints during genomic reorganization during induction of transcriptional programs. Furthermore, we hypothesize that the need to re-establish this genomic reorganization after every cell division may make proliferating cancer cells more prone to developing TOP2B-mediated double strand breaks that may contribute to genomic instability and cell-type specific rearrangements. Additionally, we envision that it may be possible to exploit these transcription-associated TOP2B mediated double strand breaks as an Achilles heel for cancer therapy. In ongoing work, we are interested in examining these hypotheses further.
Learn more about clinical trials at the Johns Hopkins Kimmel Cancer Center.
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Haffner MC, Aryee MJ, Toubaji A, Esopi DM, Albadine R, Gurel B, Isaacs WB, Bova GS, Liu W, Xu J, Meeker AK, Netto G, De Marzo AM, Nelson WG, Yegnasubramanian S. Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nature genetics. 2010;42(8): 668-75. PMCID: 3157086.
Aryee MJ, Liu W, Engelmann JC, Nuhn P, Gurel M, Haffner MC, Esopi D, Irizarry RA, Getzenberg RH, Nelson WG, Luo J, Xu J, Isaacs WB, Bova GS, Yegnasubramanian S. DNA methylation alterations exhibit intraindividual stability and interindividual heterogeneity in prostate cancer metastases. Science translational medicine. 2013;5(169): 169ra10. PMCID: 3577373.
Yegnasubramanian S, Haffner MC, Zhang Y, Gurel B, Cornish TC, Wu Z, Irizarry RA, Morgan J, Hicks J, DeWeese TL, Isaacs WB, Bova GS, De Marzo AM, Nelson WG. DNA hypomethylation arises later in prostate cancer progression than CpG island hypermethylation and contributes to metastatic tumor heterogeneity. Cancer research. 2008;68(21): 8954-67. PMCID: 2577392.
Yegnasubramanian S, Kowalski J, Gonzalgo ML, Zahurak M, Piantadosi S, Walsh PC, Bova GS, De Marzo AM, Isaacs WB, Nelson WG. Hypermethylation of CpG islands in primary and metastatic human prostate cancer. Cancer research. 2004;64(6): 1975-86.
Haffner MC, Mosbruger T, Esopi DM, Fedor H, Heaphy CM, Walker DA, Adejola N, Gurel M, Hicks J, Meeker AK, Halushka MK, Simons JW, Isaacs WB, De Marzo AM, Nelson WG, Yegnasubramanian S. Tracking the clonal origin of lethal prostate cancer. The Journal of clinical investigation. 2013;123(11): 4918-22. PMCID: 3809798.