Research Projects

Blood coagulation and cancer are intrinsically related; hypercoagulation-associated thrombotic complications like venous thromboembolism, is commonly observed in certain types of cancer including colorectal, lung, pancreatic cancer etc. which often contribute to decreased survival of such cancer patients. Colorectal cancer (CRC) accounts for ⁓10% of global cancer death every year and the rising rates of CRC morbidity in India pose a significant problem. Although hypercoagulation disorders are common in CRC, the role of coagulation factors in CRC pathogenesis is only emerging. The key molecule is activated factor X (FXa) which plays a central role in the activation of both intrinsic- and extrinsic pathway of blood coagulation. However, limited investigations characterize the actual role of FXa in cancer pathogenesis; in certain cancer types FXa promotes tumour progression whereas in others FXa limits cancer metastasis. Recent evidence indicates that FXa stimulates the growth and metastasis of CRC in murine model, and FXa-specific inhibitor, Edoxaban significantly suppresses CRC progression. However, treatment of patients with FXa-specific inhibitor often leads to hyper bleeding, resulting in the death of such patients. Therefore, understanding the underlying mechanism by which FXa promotes the development of CRC tumours becomes indispensable. From the past few decades, extracellular vesicles (EVs) have emerged as an important contributor in the progression of cancer, probably via the transfer of bioactive molecules such as proteins, lipids, mRNAs, miRNAs, metabolites etc. between the cells. However, how FXa influences the release of EVs from CRC cells and their effect in CRC pathogenesis remain ill-defined. My preliminary unpublished data reveal that FXa triggers the release of EVs from highly metastatic CRC cells. These FXa-released EVs not only promote cancer-associated thrombosis but also induce CRC progression by different mechanisms. Targeting the biogenesis of FXa-released EVs, their cargos, and EVs’ uptake by recipient cells hold promises to be an effective therapeutic strategy in the treatment of CRC and associated thrombosis beside conventional therapeutic means. Based on the preliminary findings the following aims have been proposed- Aim 1: Investigate the mechanism of EVs biogenesis by FXa. Here, we will determine the receptor(s) and intracellular signalling mechanisms involved in EV biogenesis by FXa in metastatic CRC cells. Aim 2: Determine the mechanism by which FXa-released EVs from CRC cells promote thrombosis. Here, we will focus on investigating how FXa-released EVs contribute to thrombotic outcomes in the context of CRC. Aim 3: Investigate the mechanism by which FXa-released EVs from CRC cells promote CRC progression. Here, we will determine the mechanism by which FXa-released EVs from metastatic CRC cells contribute to CRC progression. The driving factor(s) behind FXa-released EV-induced CRC progression will be identified.