John A. Martignetti, MD, PhD
Our research interests focus on gene discovery and mechanisms of genetic disease. Towards these ends, we have described a number of novel human syndromes and characterized and identified a number of genes underlying both Mendelian disorders and common cancers across four broad disease themes: 1. Cancer; 2. Osteolysis and arthritis; 3. Obesity, and; 4. Platelet disorders. Ultimately, the goals of these studies are to use the genetic information to understand the biologic pathways and networks linked to the underlying physiology and pathophysiology and then translate this knowledge into molecular-based diagnostics and therapeutics. A major focus of our work in cancer genetics has been our studies on KLF6, a tumor suppressor, and its antagonistic alternatively spliced isoform, KLF6-SV1. We originally demonstrated that a common germline SNP, associated with an increased lifetime risk of prostate cancer, results in increased expression of KLF6-SV1. Ongoing studies suggest that KLF6-SV1 is overexpressed in many different late-stage tumors and metastases, regardless of SNP-status, and that, mechanistically, KLF6-SV1 overexpression plays a causal role in increased tumor cell proliferation, angiogenesis, and most importantly, in the evasion of apoptosis. We are therefore exploring the molecular mechanisms by which these highly-relevant, KLF6-SV1-mediated cancer phenotypes are achieved and defining the therapeutic potential of targeted inhibition, through a variety of interventions, in cancers which overexpress KLF6-SV1. Exemplifying our approach in Mendelian traits, have been our studies on the “vanishing bone” syndromes, a group of inherited disorders characterized by the destruction and resorption of bones and joints. To date, the laboratory has identified four genes/loci whose mutation results in different osteolytic disorders, including the first inborn error in a matrix metalloproteinase, MMP-2, as the cause of a severe osteolysis syndrome. In parallel studies, we have also identified the genetic defect resulting in a novel bone dysplasia/osteosarcoma syndrome. The role of the recently identified tumor suppressor in osteosarcoma and multiple cancers is being examined. Beyond the study’s original intent, we are now also exploring the evolutionary implications of this disease-causing gene since it arose from an ancient retroviral integration approximately 40 MYR ago.