Research projects in our lab are focused on determining the mechanisms regulating the signal transduction and trafficking of G
protein-coupled receptors (GPCRs) in health and disease. GPCRs, targets of 60% of all pharmaceuticals, represent the largest class of cell
surface receptors in animals. GPCRs are emerging as crucial players in tumor
growth and metastasis. Cancer remains a leading cause of
morbidity and mortality, mainly due to the failure of most therapies in the
metastatic setting. To address all these issues, the
Bhattacharya lab research program involves
individual but interrelated aspects.
Lipid Signaling in Breast Cancer
We have demonstrated important functions of GPCRs for the blood-borne simple lipid lysophosphatidic acid (LPA) in promoting the metastatic spread of breast cancer cells by stimulating breast cancer migration and invasion. We have discovered important functions of GPCR adaptor proteins, beta-arrestins1/2 and the small GTPase RalA, in regulating these processes. Current projects address the mechanisms of action by which beta-arrestins regulate cancer cell invasiveness by studying the function of selected signaling molecules in regulating breast cancer metastasis, using cell model systems and animal model studies coupled with a large variety of molecular and cellular assays. These studies are funded by the Canadian Institutes of Health Research (CIHR).
Crosstalk between GPCRs and growth-factor receptors in cancer
Studies from our lab have been the first to identify a mechanism by which the signalling of the GPCR, KISS1R, originally identified to repress metastasis in several different tumors, promotes breast cancer invasion and metastatic potential. We identified that kisspeptins, endogenous ligands for GPR54 and products of the KISS1 metastasis-suppressor gene, positively regulate breast cancer invasiveness via transactivation of growth factor receptors. Current studies are investigating the underlying mechanisms by which this occurs. Elucidation of novel signaling pathways that crosstalk with growth-factor receptors may uncover new drug targets.
Regulation of placental cell invasion by small GTPases
Placental cells play a major role in implantation and formation of the placenta. The ability of invasive placental cells (trophoblasts) to properly invade into the uterus is absolutely critical for normal embryo implantation and placentation. Insufficient migration and invasion has severe consequences, resulting in diseases such as pre-eclampsia and intrauterine growth restriction, while excessive migration may lead to placenta accreta. Factors that affect trophoblast invasion will ultimately determine the success or failure of pregnancy. Many of the mechanisms regulating migration and invasion are likely shared between trophoblasts and tumor cells. Current studies are focusing on the role that small GTPases play in regulating these processes in placental cells.