Approximately 1/3 of all human cancers is of viral origin or requires viral infection as an essential cofactor. The goal of our research is to understand viral cancers; specifically, cancers that are caused by Kaposi sarcoma-associated herpesvirus (KSHV).
KSHV is a double-stranded DNA virus with over 100 open reading frames, which belongs to human herpesviruses. It was discovered in 1994 by Patrick Moore and Yuan Chang, and is associated with Kaposi sarcoma (KS) as well as a B-cell lymphoma and multicentric Castleman’s disease (MCD). These diseases are rapidly fatal as they affect internal organs. In the U.S., KS is seen in the context of immune suppression such as in HIV-positive individuals or transplant patients. In parts of Sub-Saharan Africa KS is the most common cancer in males and also seen in children.
Our lab is focused on four areas:
1 Viral Genomics – To determine the genetics of AIDS-associated cancers we have developed real-time quantitative PCR-based arrays and NextGen Sequencing approaches. These allow us to analyze patterns of gene expression and mutation. We established the UNC Vironomics core (http://www.med.unc.edu/vironomics). We also use this technology in conjunction with NextGen sequencing to study microRNAs in Kaposi sarcoma and AIDS lymphoma.
2 Hunt for new viruses – We are trying to identify novel viruses in the human population though a combination of bioinformatics and robot-assisted screening. To date, have identified a novel primate KSHV homolog in primates as well as a novel SV40 homolog.
3 Regulation of viral latency – We initially demonstrated that the KSHV latency associated nuclear antigen (LANA) is transcribed in every single KS tumor cell. LANA is required for latent viral replication and proper episome segregation. Since the LANA promoter is the major latency promoter of KSHV, we are engaged in a detailed investigation of its architecture and regulation by cellular factors, such as p53, Sp1 as well as LANA itself.
4 Mouse models of KSHV oncogenesis and pre-clinical drug development – We have developed transgenic mice, which express the LANA protein under the control of its own promoter and had previously shown that the LANA promoter exhibits B-lineage specificity in transgenic mice. We use this model in conjunction with specific ko-mice to study the immune regulation by KSHV. Building upon or initial studies of SCID-human mouse models for primary KSHV infection, we established a xenograft model for KSHV-associated lymphomas and KS. Using this model we are investigating the anti-lymphoma properties of established and novel anti-viral drugs.
Sin SH, Kim Y, Eason A, Dittmer DP. KSHV Latency Locus Cooperates with Myc to Drive Lymphoma in Mice. PLoS Pathog. 2015 Sep 1;11(9):e1005135.
Ma Z, Jacobs SR, West JA, Stopford C, Zhang Z, Davis Z, Barber GN, Glaunsinger BA, Dittmer DP, Damania B. Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses. Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):E4306-15.
Yang D, Chen W, Xiong J, Sherrod CJ, Henry DH, Dittmer DP. Interleukin 1 receptor-associated kinase 1 (IRAK1) mutation is a common, essential driver for Kaposi sarcoma herpesvirus lymphoma. Proc Natl Acad Sci U S A. 2014 Nov 4;111(44):E4762-8.
Hosseinipour MC, Sweet KM, Xiong J, Namarika D, Mwafongo A, Nyirenda M, Chiwoko L, Kamwendo D, Hoffman I, Lee J, Phiri S, Vahrson W, Damania B, Dittmer DP. Viral profiling identifies multiple subtypes of Kaposi’s sarcoma. MBio. 2014 Sep 23;5(5):e01633-14.
Yamane D, McGivern DR, Wauthier E, Yi M, Madden VJ, Welsch C, Antes I, Wen Y, Chugh PE, McGee CE, Widman DG, Misumi I, Bandyopadhyay S, Kim S, Shimakami T,Oikawa T, Whitmire JK, Heise MT, Dittmer DP, Kao CC, Pitson SM, Merrill AH Jr, Reid LM, Lemon SM. Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation. Nat Med. 2014 Aug;20(8):927-35.
Hilton IB, Simon JM, Lieb JD, Davis IJ, Damania B, Dittmer DP. The open chromatin landscape of Kaposi’s sarcoma-associated herpesvirus. J Virol. 2013 Nov;87(21):11831-42
Sin SH, Kim YB, Dittmer DP. Latency locus complements MicroRNA 155 deficiency in vivo. J Virol. 2013 Nov;87(21):11908-11.
Chugh PE, Sin SH, Ozgur S, Henry DH, Menezes P, Griffith J, Eron JJ, Damania B, Dittmer DP. Systemically circulating viral and tumor-derived microRNAs in KSHV-associated malignancies. PLoS Pathog. 2013;9(7):e1003484.
Roy D, Sin SH, Lucas A, Venkataramanan R, Wang L, Eason A, Chavakula V, Hilton IB, Tamburro KM, Damania B, Dittmer DP. mTOR inhibitors block Kaposi sarcoma growth by inhibiting essential autocrine growth factors and tumor angiogenesis. Cancer Res. 2013 Apr 1;73(7):2235-46.
Sin SH, Dittmer DP. Viral latency locus augments B-cell response in vivo to induce chronic marginal zone enlargement, plasma cell hyperplasia, and lymphoma.Blood. 2013 Apr 11;121(15):2952-63.
Chen W, Sin SH, Wen KW, Damania B, Dittmer DP. Hsp90 inhibitors are efficacious against Kaposi Sarcoma by enhancing the degradation of the essential viral gene LANA, of the viral co-receptor EphA2 as well as other client proteins. PLoS Pathog. 2012;8(11):e1003048. doi:
O’Hara AJ, Chugh P, Wang L, Netto EM, Luz E, Harrington WJ, Dezube BJ, Damania B, Dittmer DP. Pre-micro RNA signatures delineate stages of endothelial cell transformation in Kaposi sarcoma. PLoS Pathog. 2009 Apr;5(4):e1000389.
Mutlu AD, Cavallin LE, Vincent L, Chiozzini C, Eroles P, Duran EM, Asgari Z, Hooper AT, La Perle KM, Hilsher C, Gao SJ, Dittmer DP, Rafii S, Mesri EA. In vivo-restricted and reversible malignancy induced by human herpesvirus-8 KSHV: a cell and animal model of virally induced Kaposi’s sarcoma. Cancer Cell. 2007 Mar;11(3):245-58.