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Matthew J. Flick, PhD

Professor of Pathology

Our role in the Blood Research Center (BRC) is to provide a unique perspective on the contribution of coagulation and fibrinolytic factors to a wide spectrum of disease pathologies, independent of the traditional roles of these factors in bleeding and thrombosis. We utilize mouse models to analyze specific mechanisms by which proteins such as prothrombin, fibrinogen, and plasminogen contribute to the progression of inflammatory, infectious, and malignant disease. Working with our collaborative basic science and clinical partners in the BRC provides an unparalleled opportunity for rapidly advancing our understanding of the multifaceted role of the hemostatic system in hemostasis, thrombosis, and beyond.

Research Interests and Focus

  1. Pancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate of all cancers, is rapidly becoming the second leading cause of cancer deaths in the U.S., and is estimated to cost the health care system $2.4 billion each year. Patients with PDAC have a five-year survival rate of 7%, and that number drops to 2% for individuals with metastatic disease. Unfortunately, there has been little progress in shifting patient outcome over the past 40 years, highlighting the need for innovative approaches to define the molecular pathways that influence PDAC development. PDAC is typically initiated by acinar cells acquiring an activating mutation in the KRAS protooncogene, which causes cells to transition to a duct-like state known as acinar-ductal metaplasia (ADM). ADM progresses to pancreatic intraepithelial neoplasia (PanIN) lesions that develop into PDAC. A key transcriptional response to ADM/PanIN development is the dramatically increased expression of the physiological activator of the coagulation system, Tissue Factor (TF). Our research builds on a known relationship between pancreatic cancer and high-level activity of the blood coagulation system, but is unique in that it will define newly discovered mechanisms of crosstalk by which specific coagulation factors in the TME promote PDAC pathogenesis.
  2. The pervasive gram-positive bacteria Staphylococcus aureus is a common pathogen that is the causative agent for a wide spectrum of diseases including skin infections, pneumonia, bacteremia, toxic-shock syndrome and sepsis. Notably, this pathogen has evolved and maintained a number of proteins that directly engage the host hemostatic system, including factors that directly interact with the host coagulation factor fibrinogen. The long-term goal of this research program is to understand how bacterial derived proteins interact with host factors to promote bacterial virulence in the context of blood-born infections. This work will provide novel insight into the molecular pathways by which S. aureus invades and disseminates within host tissues and may shed light into novel strategies for eliminating this potentially devastating infectious agent.
  3. Obesity is a worldwide epidemic linked to numerous disease sequelae, including non-alcoholic fatty liver disease (NAFLD). This spectrum disorder can progress from the simple accumulation of triglycerides within hepatocytes (i.e., steatosis), to inflammatory steatohepatitis, to organ failure secondary to irreversible liver fibrosis and cirrhosis. Dysregulation of the coagulation system has been documented in both patients with fatty liver disease and animal models of obesity, but any contribution to disease progression has remained largely undefined. Using a murine model of high fat diet (HFD)-induced obesity, this research program is testing the hypothesis that thrombin activity and fibrin deposition drive local inflammatory events promoting the progression of obesity and obesity-associated disease sequelae. Comparative studies of wild-type mice with genetically imposed deficiencies or functional alterations in prothrombin, fibrinogen and other associated coagulation factor components suggests that the thrombin-fibrinogen axis influences obesity pathogenesis by controlling local inflammatory processes that drive metabolic inflammation leading to fibrin(ogen)-mediated HFD-induced weight gain/obesity. This research has far-reaching implications for the treatment and prevention of all the downstream sequelae of obesity and even the development of diet-mediated weight gain itself.

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Lab Members