Cellular and molecular basis of inflammation and fibrosis
Key words: inflammation, fibrosis, extracellular matrix, mouse genetics, ageing, dynamic macromolecular complexes, cell polarity, alternative splicing
This laboratory is studying the cellular and molecular basis of inflammation and fibrosis, with a particular focus on the role of stromal cells and extracellular matrix (ECM), in the context of chronic inflammatory diseases and cancer. The molecular pathways currently being studied include the adhesion receptor CD44 and its principle ligand, hyaluronan, and fibroblast activation protein (FAP), a stromal cell surface protease. Studies of CD44 and FAP are being conducted in mouse models of cancer, cardiovascular disease and pulmonary fibrosis using conditional CD44 knockout mice and FAP-null mice generated in the lab. Also the FAP promoter has been exploited to generate mice that can be used to non-invasively image reactive stromal cells in fibrotic lesions and epithelial-derived tumors, to conditionally ablate reactive stromal cells, and to manipulate gene expression specifically in fibrotic lesions and tumor stromal cells. We are studying the impact of matrix modification on cell behavior directly through regulation of receptor mediated signal transduction as well as through modulation of tissue stiffness. We are also exploring the function of CD44 and FAP in human disease.
Case, A., Brisson, B. K., Durham, A. C., Rosen, S., Monslow, J., Buza, E., Salah, P., Gillem, J., Ruthel, G., Veluvolu, S., Kristiansen, V., Puré, E., Brown, D. C., Sørenmo, K. U., Volk, S. W. Identification of prognostic collagen signatures and potential therapeutic stromal targets in canine mammary gland carcinoma PLoS One 12: e0180448, 2017.Lo, A., Li, C. P., Buza, E. L., Blomberg, R., Govindaraju, P., Avery, D., Monslow, J., Hsiao, M., Puré, E. Fibroblast activation protein augments progression and metastasis of pancreatic ductal adenocarcinoma JCI Insight 2: , 2017.Katlinski, K. V., Gui, J., Katlinskaya, Y. V., Ortiz, A., Chakraborty, R., Bhattacharya, S., Carbone, C. J., Beiting, D. P., Girondo, M. A., Peck, A. R., Puré, E., Chatterji, P., Rustgi, A. K., Diehl, J. A., Koumenis, C., Rui, H., Fuchs, S. Y. Inactivation of Interferon Receptor Promotes the Establishment of Immune Privileged Tumor Microenvironment Cancer Cell 31: 194-207, 2017. Cardiovascular consequences of prostanoid I receptor deletion in microsomal prostaglandin E synthase-1-deficient hyperlipidemic mice. Circulation : , 2016. Augmentation of CAR T-cell trafficking and antitumor efficacy by blocking protein kinase A localization. Cancer Immunology Research : , 2016. Masters In Immunology: Can targeting stroma pave the way to enhanced antitumor immunity and immunotherapy of solid tumors? Cancer Immunology Research : , 2016. A role for hyaluronan synthase 3 in the response to vascular injury. Arteriosclerosis, Thrombosis and Vascular Biology : , 2016. Type III collagen directs stromal organization and limits metastasis in a murine model of breast cancer. American Journal of Pathology : , 2015. Generation of potent T-cell immunotherapy for cancer using DAP12-based, multichain, chimeric immunoreceptors. Cancer Immunology Research : , 2015. Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Research : , 2015.