Research Projects

Pancreatic Cancer (PC) is one of the deadliest cancers that accounts for lakhs of deaths annually and has mean survival time of less than 5 years. Most of the PC deaths are associated with late diagnosis, secondary metastasis and chemoresistance. For developing effective treatment strategies, it is necessary to understand the molecular mechanisms that drive PC metastasis and chemoresistance. We recently identified Orai3 (a plasma membrane Ca2+ influx channel) as a novel regulator of PC progression. Further, we reported that Orai3 is overexpressed in PC tissue samples and higher Orai3 levels are associated with poor prognosis. However, the molecular mechanisms working downstream of Orai3 for driving PC metastasis and poor survival remain completely unappreciated. Recent literature has demonstrated a critical role of partial Epithelial to Mesenchymal Transition (pEMT) in contributing to cancer metastasis. Interestingly, a recent study reported that Ca2+ signaling plays a crucial role in inducing and maintaining pEMT. It is important to highlight that although the authors established a vital role of Ca2+ influx in inducing pEMT in PC cells, the identity of Ca2+ channel that mediates the Ca2+ influx to stimulate pEMT remains unknown. Secondly, gemcitabine alone or in combination of other drugs is one of the firstline chemotherapies used in clinical management of PC. Intriguingly, a recent study demonstrated an important role of extracellular Ca2+ entry in regulating gemcitabine resistance (GemR). However, the channel responsible for bringing Ca2+ into GemR cells is not identified yet. We analyzed the unbiased transcriptomics data generated in these two studies and found that Orai3 is overexpressed in pEMT and GemR PC cells. Hence, based on literature survey, unbiased analysis of published pEMT & GemR transcriptomics data and our preliminary studies (discussed in subsequent sections); we propose to investigate the functional significance of Orai3 in PC pEMT (enhanced metastasis) and GemR (chemoresistance). Hence, the objectives of the project are: 1.To delineate the relevance of Orai3 in pancreatic cancer pEMT. 2.To elucidate the role of Orai3 in pancreatic cancer GemR. Although Orai3 is associated with poor prognosis in PC patients, how Orai3 regulates PC prognosis remains unappreciated. Therefore, in this project we are proposing to investigate the molecular choreography that bridges Orai3 to poor PC prognosis. The knowledge generated from this project will delineate role of Orai3 in two critical determinants of PC prognosis i.e. pEMT (enhanced metastasis) and GemR (resistance against one of the first line chemotherapies). Since both metastasis and chemoresistance are associated with poor prognosis, the knowledge acquired through this project would be of high translational importance. Further, the outcome of this project would serve as a stepping stone to investigate and design strategies to target Orai3 for better clinical management of PC.