B.A. in Microbiology - Southern Illinois University
M.S. in Microbiology - Colorado State University
Ph.D. in Biochemistry - Harvard Medical School
Postdoctoral Fellow - ARIAD Pharmaceuticals and Harvard Medical School
Assistant/Associate Professor - Van Andel Research Institute
Professor, Dept of Cellular and Molecular Medicine, University of Arizona
The research in my lab is focused on understanding the mechanisms by which the tumor microenvironment influences prostate cancer development, metastasis, and hormonal drug resistance. Our approach is to understand the normal biology of the prostate gland and its microenvironment, as well as the bone environment, to inform on the mechanisms by which tumor cells remodel and use that environment to develop, metastasize, and acquire hormonal resistance. We use a combination of genetics, cell biology, and molecular biology in in vitro and in vivo models of prostate cancer to understand basic underlying mechanisms. Our hypotheses and approaches are based solidly on observations derived from clinical disease and are aimed at addressing clinically important problems in prostate cancer. Our current research program revolves around three primary areas of interest.
We are using bioengineering approaches to develop human in vitro models that better represent human prostate cancer as it is seen in the clinic. We developed the first Prostate-on-a-Chip model that recapitulates the development and differentiation processes that occur in the normal prostate gland. We are using this model to define how signals from oncogene-transformed epithelium influence androgen signaling in the underlying stroma and how dysregulation of that stromal signaling potentiates prostate cancer progression. We are also using this model to define the underlying genetic and epigenetic events that are dysregulated during prostate cancer development. Our long-term goal is to use these models to define new biomarkers that can help prostate cancer patients make better decisions about treatment.
For prostate cancer patients who develop metastatic disease, the primary site of metastasis is the bone. We are investigating the signaling pathways that promote and maintain bone metastases. Key pathways we have identified in this process include integrin α6, CD82, Notch3, and the androgen receptor (AR). Current studies are focused on defining the relationship between Snail and AR how they cooperatively work together to control tumor cell dissemination and metastatic outgrowth. We are particularly interested in how the bone microenvironment influences metastatic processes.
Castration-Resistant Prostate Cancer (CRPC)
Anti-androgen therapy that targets the androgen receptor (AR) is the mainstay for prostate cancer patients with bone metastatic disease. Unfortunately, the majority of these patients will relapse with drug resistance, referred to as CRPC. Interestingly, AR is still the major driver of CRPC, the gene being mutated, amplified, or activated in ways that no longer require androgen. We are investigating how signals from the bone tumor microenvironment potentiate AR and integrin α6 signaling to perpetuate tumor growth and tumor survival during hormonal drug resistance. We discovered that the hypoxic environment of the bone contributes to drug resistance through induction of Bnip3 and PIM kinase via AR and integrin α6 to promote mitophagy and anti-ROS signaling. We are developing novel therapies to target AR, integrin α6, and PIM and testing them in human patient-derived bone metastasis models.