Defining and targeting subtype specific inflammatory drivers in pancreatic cancer
Chronic inflammation is an important risk factor for the development of pancreatic ductal adenocarcinoma (PDAC) and activation of inflammatory pathways that drive tumor growth, trigger metastatic dissemination and mediate drug resistance are hallmarks of the disease. The molecular and cellular mechanisms linking the immune system with pro-tumorigenic signaling pathways in the tumor cells and their microenvironment are poorly defined.
Our preliminary data using genetically engineered mouse models (GEMMs) provide evidence that PDAC subtype specific oncogenic drivers as well as secondary molecular events reprogram and educate the tumor stroma and immune system to drive tumor progression in a highly context specific fashion. We will systematically dissect inflammatory signals derived from defined tumor subtypes and their microenvironment and investigate how these signals influence PDAC progression, therapeutic efficacy and treatment resistance. Ultimately, we will generate novel third-generation GEMM systems allowing us to manipulate lymphocyte subpopulations with high efficiency independently of the driving oncogene.
With our experiments, we aim to uncover targetable inflammatory drivers and develop novel treatment strategies for translation into the clinic in the future.
Falcomata, C., Barthel, S., Schneider, G., Saur, D., and Veltkamp, C. (2019). Curr Opin Genet Dev 54, 97-104
Weber, J., de la Rosa, J., Grove, C. S., Schick, M., Rad, L., Baranov, O., Strong, A., Pfaus, A., Friedrich, M. J., Engleitner, T., Lersch, R., Ollinger, R., Grau, M., Menendez, I. G., Martella, M., Kohlhofer, U., Banerjee, R., Turchaninova, M. A., Scherger, A., Hoffman, G. J., Hess, J., Kuhn, L. B., Ammon, T., Kim, J., Schneider, G., Unger, K., Zimber-Strobl, U., Heikenwalder, M., Schmidt-Supprian, M., Yang, F., Saur, D., Liu, P., Steiger, K., Chudakov, D. M., Lenz, G., Quintanilla-Martinez, L., Keller, U., Vassiliou, G. S., Cadinanos, J., Bradley, A., and Rad, R. (2019). Nat Commun 10, 1415