Prasenjit Dey

Research Overview:

The tumor microenvironment remains a challenging area of research, because of the large number of actors such as myofibroblasts (MF), extracellular matrix (ECM), and immune cells interacting in a dynamic fashion with the cancer cells that determines the overall outcome. Our research is primarily focused on understanding how tumor microenvironment factors such as cytokines and chemokines synergize with tumor intrinsic oncogenic pathways for tumor initiation and survival.

Role of CD4+ T cells in pancreatic cancer progression.

A hallmark feature of PDAC is an extensive desmoplastic stroma comprised of myofibroblasts (MF), extracellular matrix (ECM), and immune cells. Among the infiltrating immune cells, the study is mainly focused on cytotoxic T cells, NK cells and M1 macrophages in inhibiting tumor initiation and progression. Less explored is the potential role of the immune cells, which are early responders to the mutation events in PDAC, especially CD4+ T cell in disease promotion. CD4+ T helper cells, with its multiple subtypes (TH 1, 2, 9, 10, 17, 22) are critical for inflammatory processes in cancer. Among them, TH2 subtypes can promote tumor growth via various mechanisms that include induction of M2 macrophage polarization.

Recently, we have identified a unique role of TH2 polarized CD4 T-cells in collaborating with oncogenic Kras in transforming indolent PanIN into malignant pancreatic tumor. Our data show an important role of tumor infiltrating TH2 cells and its prototypic cytokines IL4 and IL13 driving tumor initiation and progression. Concurrently, oncogenic Kras upregulates the expression of cytokine receptors IL2rg, IL4ra and IL13ra1 that, upon IL4 and IL13 engagement, activates the Jak1-Stat6 pathway. The goal of this project is to identify factors that are released by cancer cells that attract TH2 cells into the tumor microenvironment and if blocking of TH2 infiltration mediated pathway has any therapeutic benefit.

Cytokine mediated metabolic reprogramming in cancer.

A major component of tumor microenvironment is the secreted factors arising from infiltrating immune cells, stroma and cancer cells itself, which shapes the overall trajectory of the disease. Transcriptomic analysis has identified cMyc upregulation upon treatment with IL4 or IL13. In agreement with cMyc roles in influencing tumor metabolism, targeted metabolomic analysis have shown an increase in glycolysis upon treatment with IL4 or IL13. In consistence with increase in glycolysis upon IL4 or IL13 treatment, there is an increase in expression of glycolytic enzymes (Hexokinase II, lactate dehydrogenase and pyruvate dehydrogenase). This data is especially intriguing because prior in vitro studies failed to capture the dependence of cancer cells on glycolysis, probably because of the absence of these vital cytokines in vitro culture media forcing the cancer cells to utilize glutamine as carbon source. The goal of this project is to investigate the role of IL4 and/or IL13 in driving an alternative metabolic circuit especially the acceleration of glycolytic pathways. We will determine whether cMyc mediated metabolic shift is essential for cancer cell survival. We will use biochemical and metabolic techniques to understand whether cMyc increases the glucose consumption which contributes to cancer cell biomass leading to aggressive tumor growth.

Dey Lab