Current Research

The major research areas of the lab are experimental cancer therapeutics, tumor microenvironment, and cancer bone metastasis for over 15 years with strong collaborators in these fields both within UAB and outside, and published several papers.  In particular reference to cancer-bone interaction, we model breast cancer (BCa) 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 (MSCs) as effective therapeutic vehicles for bone remodeling in BCa osteolytic pathology (Clin. Cancer Res. 2009). We further identified signals that would result in bone-enriched homing of MSC and shown by targeting, enhanced homing of therapeutic MSCs to the bone (FASEB J 2007). 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 mutant that lacks TRAIL binding affinity and validated in vivo in a disseminated osteolytic malignancy model in immunodeficient mice (Mol. Cancer Res. 2015; Blood Adv. 2017). We were the first group to identify a subset of immature myeloid cells, known as myeloid-derived suppressor cells (MDSCs), in the tumor microenvironment (TME) within the bone directly undergo osteoclast differentiation and serve as osteoclast progenitors to enhance bone damage (Cancer Res. 2013). Further, 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 we developed resulted in a shift in the immune milieu favoring anti-tumor cytokines and chemokines (Mol. Cancer Ther. 2020). Towards understanding the mechanism of intercellular cross-talk between breast cancer cells and macrophage progenitors, we recently adopted a 3D matrigel bioreactor system and identified that RANKL promotes autocrine and paracrine signaling effects to cause M2 macrophage polarization. Further, as shown in preliminary studies of this application, we identified that extracellular vesicles (exosomes), released by RANKL stimulated breast cancer cells play an important role in altering macrophage phenotype through non-coding microRNA. Our collaborative studies with expertise in exosomes have recently been published (Lab Investigation 2020; Frontiers in Medicine 2021). Click here for additional publications.