Welcome to the Ponnazhagan lab
The major focus of research in our lab are breast and prostate cancers on areas of tumor microenvironment (TME), experimental cancer therapeutics, cancer bone metastasis, and stem cells. We model breast cancer to adopt strategies that target tumor cells, immune suppression, and aggressive osteoclast functions. To overcome limitations in current therapies, we have developed novel molecular tools and targeted delivery mechanisms. We have developed strategies to utilize mesenchymal stem cells (MSC) as effective therapeutic vehicles for bone remodeling in breast cancer osteolytic pathology. We identified signals that would result in bone-enriched homing of MSC and shown by targeting, enhanced homing of therapeutic MSCs to the bone. Towards targeting receptor activator of nuclear factor kappa-B ligand (RANKL) activation using osteoprotegerin (OPG), a decoy receptor for RANKL without interfering TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis of tumor cells, more recently by structural homology modeling, we developed an OPG variant that lacks TRAIL binding affinity and validated in vivo in a disseminated osteolytic malignancy model. We are the first group to identify a subset of immature myeloid cells, known as myeloid-derived suppressor cells (MDSCs), in the TME within the bone directly undergo osteoclast differentiation and serve as osteoclast progenitors to enhance bone damage. We recently established the role of RANKL in activating M2 macrophages in breast cancer microenvironment and dampening the effects of elevated RANKL, using the OPG variant we developed resulted in a shift in the immune milieu favoring anti-tumor cytokines and chemokines. In prostate cancer, we study prostate cancer biology/immunology, molecular mechanisms of castration-resistant disease, bone metastasis, and test targeting tumor angiogenesis and androgen receptor function by experimental therapeutics.
