Diverse alterations involving the androgen receptor locus (gene and enhancer) seen on linked-read whole genome sequencing of castration-resistant prostate cancer (from Viswanathan*, Ha*, Hoff* et al. Cell, 2018)
Overview and Research Motivation The genomics revolution has given us the power to understand the molecular wiring of cancer cells in unprecedented detail, and has enabled the development of highly effective targeted therapies that rationally perturb specific molecular pathways essential to the cancer cell. Still, there are many open questions whose answers would significantly improve the resolution at which we understand how cancer develops and progresses. For example – 1) What are the significant drivers of cancer that occur in non-coding or “dark” regions of the genome, and how can these be rationally targeted?; 2) How does the genome or transcriptome of a cancer cell adapt to pressure from cancer therapies?; 3) How do changes in the cancer genome interact with changes at other levels of gene regulation (transcription, RNA processing/modification, RNA splicing) to remodel the malignant transcriptome? We are interested in exploring these and other fundamental questions in cancer biology using multidisciplinary and collaborative approaches, with the ultimate goal of laying the pre-clinical foundation for the next generation of targeted therapies that can improve outcomes for cancer patients.
We have several exciting research projects available in the broad areas below. Approaches range from genomics (dry-lab) to functional experimentation (wet-lab) to clinical/translational efforts. Please contact Dr. Viswanathan if you are interested in joining or collaborating with the lab.
Mapping the Genome and Transcriptome of Genitourinary Cancers Recent large-scale sequencing efforts have been instrumental in delineating the most significantly mutated cancer genes across many common cancer types. Still, many of these efforts have primarily interrogated coding sequences, which constitute only a small fraction (<2%) of the genome. Many alterations in noncoding or poorly mappable regions of the cancer genome may hence remain to be discovered. For example, using whole genome sequencing, we recently described highly-recurrent duplications involving a novel long-range enhancer of the androgen receptor, seen in > 80% of cases of castration-resistant prostate cancer.
We are interested in employing bleeding-edge genome and transcriptome sequencing methodologies on tumor samples and cell-free DNA to comprehensively map the alterations that drive genitourinary cancers. We are particularly interested in understanding how somatic alterations in cancer genomes can contribute to and reshape the malignant transcriptome. These studies are aimed at improving our understanding of the drivers of genitourinary cancers with the goal of informing the development of improved diagnostics and therapeutic targets in these diseases.
Top: Paralog vulnerabilities identified from analysis of genome-scale genetic screening of cancer cell lines by shRNA (top-left) or CRISPR (top-right).
Bottom: Transcriptomic changes seen upon MAGOHB knockdown in either a MAGOH-deleted (bottom-left) or MAGOH-replete (bottom-right) genetic context.
Identifying Novel Molecular Vulnerabilities of Genitourinary Cancers The capacity to integrate genomic and transcriptomic features of cancer cell line models with functional genetic perturbation performed at genome-scale has yielded an unprecedented ability to precisely map the molecular contexts in which cancers display specific (and often unexpected) molecular vulnerabilities. For example, redundant essentiality between paralog genes may be therapeutically exploited when one of two copies of an essential paralog pair is somatically deleted in cancer. We have recently reported several such paralog pairs, including the example of MAGOHB, a component of the exon-junction complex that proves essential to maintaining RNA surveillance when its paralog, MAGOH, is somatically deleted. By performing genome-scale genetic screening in models of genitourinary cancer, we aim to uncover novel and therapeutically tractable molecular targets that can inspire the development of the next-generation of therapies for these cancers.