Research Projects

Pancreatic ductal adeno carcinoma (PDAC) ranks fourth in cancer related mortality in the United States, with forecasts suggesting it may ascend to the second position by the year 2030 [1]. Pancreatic stellate cells (PSCs) are myofibroblast-like cells found within the pancreatic tumor microenvironment (TME) that play a significant role in the desmoplastic response associated with PDAC [2]. Normally, PSCs are in a quiescent state within the pancreas; however, upon activation they significantly contribute to the progression of PDAC by increasing the release of growth factors and producing a considerable extracellular matrix (ECM) [3, 4]. These cells engage in persistent interactions with pancreatic cancer cells, becoming vital to their biological behavior and aiding in tumor progression and resistance to chemotherapy [5]. Increasing evidence suggests that targeting PSCs represents a promising therapeutic approach to disrupt pancreatic tumor-stroma interactions [6-9]. Among the various factors that promote tumor growth, cyclin-dependent kinase 5 (CDK5), a proline-directed serine/threonine kinase, is highlighted as a promising target for cancer therapy across multiple cancer types [10-15]. While few studies have investigated the role of CDK5 in PDAC, there has been a lack of focus on its role in CAFs. In CAFs, CDK5 activation during HOTARI long non-coding RNA-induced epithelial-mesenchymal transition (EMT) correlates with H3K27 trimethylation at the CDK5RAP1 promoter, an inhibitor of CDK5 [16, 17]. Additionally, recent study has revealed the presence of CDK5 not only within the tumor mass of human breast cancer specimens but also in the adjacent TME [18]. These findings suggest that CDK5 may have an important role in cancer metastasis through its interactions with the TME. Hence, our current project is focused on exploring the function of CDK5 in the activation of PSCs. Here we will assess whether CAF cells activated by CDK5 can contribute to malignancy and EMT in PDAC cells, as well as identify the signaling pathways that are implicated. The key questions we aim to address include: Does CDK5 kinase facilitate the transdifferentiation of pancreatic fibroblasts into myofibroblasts or cancer-associated fibroblasts in vitro, and can the knockdown of CDK5 impede this transformation? If so, do pancreatic myofibroblasts that overexpress CDK5 enhance malignancy in epithelial cells and promote tumor growth in both in vitro and in vivo environments? Is the paracrine IL-6 signaling, induced by stellate cells in PDAC cells via the IL-6/JAK/STAT-3 pathway, regulated by CDK5? This study is expected to yield important insights into the interactions between tumor and stroma in pancreatic cancer and will assess the therapeutic potential of a CDK5 inhibitor. The insights gained from this study are expected to lead to innovative therapeutic strategies for the treatment and management of pancreatic cancer, as well as other stroma rich cancers.