Matthew J. Flick, PhD

Member, Division of Experimental Hematology & Cancer Biology

Academic Affiliations

Associate Professor, UC Department of Pediatrics

Phone 513-636-6628

Fax 513-803-5095


Coagulation factors and inflammatory diseases

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.

BS: Xavier University, Cincinnati, OH.

PhD: Purdue University, West Lafayette, IN.

Post-doctoral Fellow: Cincinnati Children’s Hospital and Medical Center, Division of Developmental Biology, Cincinnati, OH.

View PubMed Publications

Shaw MA, Kombrinck KW, McElhinney KE, Sweet DR, Flick MJ, Palumbo JS, Cheng M, Esmon NL, Esmon CT, Brill A, Wagner DD, Degen JL, Mullins ES. Limiting prothrombin activation to meizothrombin is compatible with survival but significantly alters hemostasis in mice. Blood. 2016 Aug 4;128(5):721-31.

Ko YP, Flick MJ. Fibrinogen Is at the Interface of Host Defense and Pathogen Virulence in Staphylococcus aureus Infection. Semin Thromb Hemost. 2016 Jun;42(4):408-21.

Joshi N, Kopec AK, Ray JL, Cline-Fedewa H, Nawabi A, Schmitt T, Nault R, Zacharewski TR, Rockwell CE, Flick MJ, Luyendyk JP. Fibrin deposition following bile duct injury limits fibrosis through an αMβ2-dependent mechanism. Blood. 2016 Jun 2;127(22):2751-62.

Motley MP, Madsen DH, Jürgensen HJ, Spencer DE, Szabo R, Holmbeck K, Flick MJ, Lawrence DA, Castellino FJ, Weigert R, Bugge TH. A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo. Blood. 2016 Mar 3;127(9):1085-96.

Yuasa M, Mignemi NA, Nyman JS, Duvall CL, Schwartz HS, Okawa A, Yoshii T, Bhattacharjee G, Zhao C, Bible JE, Obremskey WT, Flick MJ, Degen JL, Barnett JV, Cates JM, Schoenecker JG. Fibrinolysis is essential for fracture repair and prevention of heterotopic ossification. J Clin Invest. 2015 Sep;125(9):3723.

Adams GN, Rosenfeldt L, Frederick M, Miller W, Waltz D, Kombrinck K, McElhinney KE, Flick MJ, Monia BP, Revenko AS, Palumbo JS. Colon Cancer Growth and Dissemination Relies upon Thrombin, Stromal PAR-1, and Fibrinogen. Cancer Res. 2015 Oct 1;75(19):4235-43.

Prasad JM, Gorkun OV, Raghu H, Thornton S, Mullins ES, Palumbo JS, Ko YP, Höök M, David T, Coughlin SR, Degen JL, Flick MJ. Mice expressing a mutant form of fibrinogen that cannot support fibrin formation exhibit compromised antimicrobial host defense. Blood. 2015 Oct 22;126(17):2047-58.

Yuasa M, Mignemi NA, Nyman JS, Duvall CL, Schwartz HS, Okawa A, Yoshii T, Bhattacharjee G, Zhao C, Bible JE, Obremskey WT, Flick MJ, Degen JL, Barnett JV, Cates JM, Schoenecker JG. Fibrinolysis is essential for fracture repair and prevention of heterotopic ossification. J Clin Invest. 2015 Aug 3;125(8):3117-31.

Joshi N, Kopec AK, O'Brien KM, Towery KL, Cline-Fedewa H, Williams KJ, Copple BL, Flick MJ, Luyendyk JP. Coagulation-driven platelet activation reduces cholestatic liver injury and fibrosis in mice. J Thromb Haemost. 2015 Jan;13(1):57-71.

Raghu H, Cruz C, Rewerts CL, Frederick MD, Thornton S, Mullins ES, Schoenecker JG, Degen JL, Flick MJ. Transglutaminase factor XIII promotes arthritis through mechanisms linked to inflammation and bone erosion. Blood. 2015 Jan 15;125(3):427-37.

NIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases Research. Director. Cincinnati Rheumatic Diseases Core Center. Aug 2011-Jun 2016. 2P30 AR47363.

Hemostatic factors and sickle cell disease. Co-investigator. NIH. Dec 2011-Nov 2016. R01 HLI12603.