About Us | Dittmer Lab

Research interests at Dittmer Lab

By current estimates, 25-35% of all human cancers have viral origin or require viral infection as an essential cofactor. Our research goal focuses on understanding viral tumorigenesis, specifically cancers caused by Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8). KSHV is a double-stranded DNA virus of about 120kbp, belonging to the rhadinovirus family of human herpesviruses.

Discovered in 1994, KSHV is associated with Kaposi’s sarcoma (KS) as well as B-cell lymphoproliferative diseases like pleural effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD). These diseases affect internal organs and are ultimately fatal; they are usually seen in the U.S. among immunosuppressed individuals like HIV-positive individuals and transplant patients.

Mouse models of KSHV oncogenesis

We have developed transgenic mice that express the LANA protein under the control of its promoter after previously showing that the LANA promoter exhibits B-lineage specificity in transgenic mice (J.Virol 76:11024pp (2002)). Offspring from multiple independent founder animals develop follicular B-cell proliferative disorders. Thus, our lab has established the first in vivo model for KSHV LANA-dependent tumorigenesis. We established a xenograft model for KSHV-associated lymphomas, building upon our initial studies of SCID-human mouse models for primary KSHV infection (J.Exp.Med. 190:1857pp (1999)). Using this model, we continue investigating the anti-lymphoma properties of established and novel anti-viral drugs (Cancer Res. 64:4790pp (2004)). Most recently, we developed transgenic mice that contain the entire KSHV virus and developed Kaposi Sarcoma Cell Host Microbe . 2024 May 8;32(5):755-767.

Transcriptional profiling of AIDS-associated cancers

We have developed real-time quantitative PCR-based arrays to determine the contribution of viral genes in AIDS-associated cancers, which allow us to analyze KSHV transcript patterns in PEL and KS (Cancer Res. 63:2010pp (2003)). This technology has allowed us to design viral arrays for all human herpes viruses. We are using this approach in collaboration with physicians and researchers at the UNC Lineberger Comprehensive Cancer Center, the NCI-AIDS Malignancy Clinical Trials Consortium, the NCI Intramural Viral Epidemiology Group, the Memorial Sloan-Kettering Cancer Center, and the University of Miami Cancer Center, to determine the transcriptional responses of EBV and KSHV-associated lymphomas to novel anti-cancer regimens in culture, in mouse models, and patients.

Identification of new viruses

Based on our expertise in high-throughput PCR, we are trying to identify novel viruses in the human population. We tested our strategy using baboons and successfully identified a novel primate KSHV homolog in baboons (J.Virol.77:8159pp (2003)) and a novel SV40 homolog. We have since established bioinformatics and robotics infrastructures to screen and rapidly quantify virtually all known viruses. This approach has allowed us to identify novel West Nile viruses (J.Clin.Microbio 42:1511pp (2004)) and continue studying West Nile inhibitors and novel vaccines.

Summary

In sum, our cancer-related efforts seek to combine translational studies of KSHV-associated cancers with appropriate mouse models and detailed molecular investigations of a few critical viral oncogenes. Using high-throughput real-time quantitative PCR as the signature technology platform for this group, we can rapidly cross-validate the results of these three approaches to cancer research.