Dwinell Laboratory Research Areas
Chemokines functionally maintain immune homeostasis, control leukocyte trafficking in inflammation and play key roles in the movement of cells during development, angiogenesis, and tumor progression. Chemokines are a large family of secreted proteins that prototypically direct the trafficking of immune cells during immune responses and control the spatial and temporal intensity of inflammation. The process of cellular movement along a concentration gradient, called chemotaxis, relies on a chain of signaling events, initiated when the chemokine binds its cognate G protein-coupled receptor (GPCR). Activated chemokine receptors communicate with G protein and b-arrestin proteins inside the cell which initiate organized rearrangement of the cytoskeleton and other cellular components to cause the cell to move along an extracellular gradient of increasing concentration to the cellular source of the chemokine. Solid and liquid tumors, through an accumulation of genetic alterations, acquire the ability to hijack the chemokine communication pathway, resulting in the movement of tumor cells away from the primary growth and towards new tissues that highly express the chemokine ligand, a process known as metastasis. Chemokine production within the primary tumor alters the tumor immune microenvironment, contributing to immune suppression and cancer progression.
Current Research Projects
1. Inflammatory Tumor Microenvironment. My NIH-funded research program remains focused on the immune messengers that direct immune cell, stromal cell and epithelial cell roles in inflammation, host defense and tumor immune evasion. Our work established that regulated production of chemokines, secreted molecules that direct the trafficking of immune cells are key effectors influencing the spatial and temporal intensity of mucosal inflammation. We were among the first to demonstrate a positive feedback loop for interferon-regulated expression of the chemokines CXCL9, CXCL10, and CXCL11 in the trafficking of T cells into the inflamed gut. We have recently determined that the desmoplastic stroma of human and mouse pancreatic cancers express an array of inflammatory chemokines, most notably CCL28 and CXCL17. These findings are important as the dense desmoplasia is a unique and clinically salient feature of human pancreatic cancer. Ongoing investigations seek to uncover the functional roles for immune messengers (chemokines), receptors (STING), and metabolic poisons in remodeling the immune suppressed stromal microenvironment of solid and hematologic tumors.
2. Chemokines in Inflammation and Cancer. Some of our earliest work defined for the first time that the chemokine CXCL12 was epigenetically silenced in cancer. Mechanistically, we demonstrated that the Cxcl12 gene contains 3 large CpG islands, which in colon, breast, and pancreas cancer, were hypermethylated by Dnmt enzymes. We went on to establish that epigenetic silencing through DNA hypermethylation of the Cxcl12 gene established a cancer cell permissive for tumor metastasis in vivo. These reports effectively shifted the paradigm that chemokine receptor expression was the predominant determinant of cancer metastasis. Recent work in the laboratory is exploring mechanisms whereby epigenetic changes modulate expression of additional chemokines in inflamed tissues or pancreatic cancer. We have concomitantly studied the expression and signaling of chemokine receptors. In work initially supported by the NIDDK we were among the first to describe expression of the chemokine receptor CXCR4 by non-hematological cells. This work became the foundation for abundant subsequent research showing CXCR4 expression on an array. Ongoing studies seek to exploit CXCR4 expression and signaling to selectively promote wound healing in gut and skin inflammation and/or abrogate tumor cell metastasis of inflammation-associated cancers. Current work supported by an NCI grant is examining biased agonist signaling as a pharmacologic mechanism that mechanistically explains pleiotropic effects of CXCR4 in cancer.
3. Energy Metabolism in Cancer. A fundamental property of the human body is the movement of cells within and between tissues. Cell movement and migration may have beneficial effects, for example in wound healing or leukocyte trafficking, or deleterious effects, such as in the invasion and metastasis of tumor cells. Our recent work demonstrates that chemokine biased agonist signaling stimulates a non-motile cellular response we call ataxia through the activation of an AMPK energy sensing molecular brake. A recent NCI-funded award led to the discovery that mitochondria-targeted respiration inhibitors abrogate cancer cell proliferation through multiple mechanisms including disruption of cell cycle regulators and activation of mitophagy through the activation of an AMPK energy sensing molecular brake. Moreover, we have recently demonstrated that inhibition of bioenergetic metabolism potently activates proinflammatory anti-tumor immune responses, while simultaneously activating tumor infiltrating T cells. Ongoing work seeks to determine if these tumor selective metabolic inhibitors synergistically inhibit tumor progression through tumor intrinsic inhibition of cancer cell proliferation and production of chemokine gradients withing the tumor parenchyma needed for anti-tumor immune responses.
4. Translational Research. A principal goal of my current research program is to investigate and translate mechanistic analyses of chemokine signaling to advance human health by enhancing beneficial cell movement and limiting harmful migration of cells. Continuing multidisciplinary research in my laboratory seeks to exploit cellular or metabolic vulnerabilities within the tumor immune microenvironment. To this end we have discovered that chemokines can bind their cognate receptors and act as biased agonists, activating different signaling pathways and functional growth, apoptosis, or migration responses to disrupt cancer cell metastasis. Our recent work has dissected mechanisms by which STING agonists drive chemokine production in pancreatic cancer. We have also initiated drug development studies of new, rationally designed, mitochondria-targeted compounds to selectively disrupt cancer cell proliferation, stimulate production of physiologically relevant chemokine gradients needed for anti-tumor immunity, and regulate immune cell activation within the tumor microenvironment.