Dominic Smiraglia, PhD

My lab has two major themes over-arching my research program. The first is the idea that epigenetic modifications provide an exceptional route for cancer cell ‘evolution’ as cancers progress to advanced phenotypes. The second is the idea that epigenetic regulation is the means by which the genome can be responsive to the environment. These themes overlap in the sense that the environmental challenges to cancer cells change during tumor progression as they are required to adapt to metabolic pressures, such as hypoxia, and stress on nucleotide pools. Further challenges come with changes in cell-cell interactions as cells leave their normal stromal interactions and metastasize. In the case of a hormone responsive tumor like prostate cancer, the environmental changes also include changes in hormonal stimulation and nuclear receptor action. Such environmental stresses, or challenges, are key to providing the selective pressures that are required to drive ‘evolution’ of cancers cells, making them adept at progressing to more advanced phenotypes. I have an established track record in molecular genetics with a strong focus on DNA methylation in cancer. Specifically in prostate cancer, I have many years of experience studying epigenetic deregulation in both human and mouse models. Over the last ten years I have expanded these efforts into understanding folate biology, polyamine metabolism, and one-carbon metabolism in prostate cancer and how this influences genome integrity and DNA methylation. Additional efforts are to expand these lines of research towards studies into the effect of dietary folate modulation, as well as pharmacological manipulation, on prostate cancer development and progression to advanced phenotypes in transgenic mouse models and human xenograft models. These efforts intersect with our studies into how epigenetic reprogramming of enhancers contributes to lineage plasticity as a means of escape from the control of androgen deprivation therapy, as folate and polyamine metabolism significantly impact acetyl- and methyl- donor pools required to for epigenetic regulation of the genome.

Over the last ten years my research trajectory has been leading to combining our research into basic epigenetic mechanisms with our studies on metabolism and development of novel therapeutic strategies leveraging metabolism. Recent studies into pharmacological manipulation of polyamine catabolism and the methionine salvage pathway have explored novel therapeutic strategies to treat advanced stages of prostate cancer. Concurrently, we have been studying the role of epigenetic dysregulation in the development of advanced stage prostate cancer. Thus, my lab is uniquely positioned to extend our past work by exploring how metabolic adaptation to drug induced stress can be propagated to the epigenome. We aim to provide key mechanistic insight into the intersection between two fundamental processes driving tumorigenesis; metabolic adaptation and epigenomic reprogramming. This will provide novel insights into how to leverage the metabolic effects on the epigenome for better epigenetic therapy.