Department of Pathology, The University of Alabama at Birmingham, USA;Dr. Ponnazhagan is a trained molecular geneticist with a focus on cancer. He is currently a Full Professor and holds an Endowed Professorship in Experimental Cancer Therapeutics. The major research areas of Dr. Ponnazhagan’s lab are experimental cancer therapeutics, including stem cell and gene therapy using adeno-associated virus (AAV), tumor microenvironment (TME), and cancer bone metastasis. In reference to cancer-bone interaction, Dr. Ponnazhagan’s lab models breast cancer to adopt strategies that target tumor cells, immune suppression, and aggressive osteoclast functions. To overcome limitations in current therapies, his lab developed novel molecular tools and targeted delivery mechanisms, utilizing mesenchymal stem cells as effective therapeutic vehicles for bone remodeling in breast cancer osteolytic pathology. Towards targeting receptor activator of nuclear factor kappa-B ligand (RANKL) activation using osteoprotegerin (OPG), a decoy receptor for RANKL, without interfering in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis of tumor cells, his lab developed an OPG mutant by structural protein engineering that lacks TRAIL binding affinity and validated in vivo in a disseminated osteolytic malignancy model. His group is the first one to identify a subset of immature myeloid cells, known as myeloid-derived suppressor cells, in the TME within the bone, directly undergo osteoclast differentiation and serve as osteoclast progenitors to enhance bone damage. Recent studies from his lab established the role of RANKL in activating M2 macrophages in breast cancer microenvironment and that dampening the effects of elevated RANKL using the OPG mutant resulted in a shift in the immune milieu favoring an anti-tumor cytokines and chemokine response.