Project P06
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.
Publications
Falcomata, C., Barthel, S., Schneider, G., Rad, R., Schmidt-Supprian, M., and Saur, D. (2023). Cancer Discov 13, 278-297. doi: 10.1158/2159-8290.CD-22-0876
Schmitt, C., Saur, D., Barthel, S., and Falcomata, C. (2022). J Vis Exp. doi: 10.3791/64253
Randriamanantsoa, S., Papargyriou, A., Maurer, H. C., Peschke, K., Schuster, M., Zecchin, G., Steiger, K., Ollinger, R., Saur, D., Scheel, C., Rad, R., Hannezo, E., Reichert, M., and Bausch, A. R. (2022). Nat Commun 13, 5219. doi: 10.1038/s41467-022-32806-y
Braun, C. J., Adames, A. C., Saur, D., and Rad, R. (2022). Nat Protoc 17, 1903-1925. doi: 10.1038/s41596-022-00700-y
Giansanti, P., Samaras, P., Bian, Y., Meng, C., Coluccio, A., Frejno, M., Jakubowsky, H., Dobiasch, S., Hazarika, R. R., Rechenberger, J., Calzada-Wack, J., Krumm, J., Mueller, S., Lee, C. Y., Wimberger, N., Lautenbacher, L., Hassan, Z., Chang, Y. C., Falcomata, C., Bayer, F. P., Barthel, S., Schmidt, T., Rad, R., Combs, S. E., The, M., Johannes, F., Saur, D., de Angelis, M. H., Wilhelm, M., Schneider, G., and Kuster, B. (2022). Nat Methods 19, 803-811. doi: 10.1038/s41592-022-01526-y
Orben, F., Lankes, K., Schneeweis, C., Hassan, Z., Jakubowsky, H., Krauss, L., Boniolo, F., Schneider, C., Schafer, A., Murr, J., Schlag, C., Kong, B., Ollinger, R., Wang, C., Beyer, G., Mahajan, U. M., Xue, Y., Mayerle, J., Schmid, R. M., Kuster, B., Rad, R., Braun, C. J., Wirth, M., Reichert, M., Saur, D., and Schneider, G. (2022). JCI Insight 7. doi: 10.1172/jci.insight.151353
Roy-Luzarraga, M., Reynolds, L. E., de Luxan-Delgado, B., Maiques, O., Wisniewski, L., Newport, E., Rajeeve, V., Drake, R. J. G., Gomez-Escudero, J., Richards, F. M., Weller, C., Dormann, C., Meng, Y. M., Vermeulen, P. B., Saur, D., Sanz-Moreno, V., Wong, P. P., Geraud, C., Cutillas, P. R., and Hodivala-Dilke, K. (2022). Cancer Res 82, 1909-1925. doi: 10.1158/0008-5472.CAN-20-3807
Peschke, K., Jakubowsky, H., Schafer, A., Maurer, C., Lange, S., Orben, F., Bernad, R., Harder, F. N., Eiber, M., Ollinger, R., Steiger, K., Schlitter, M., Weichert, W., Mayr, U., Phillip, V., Schlag, C., Schmid, R. M., Braren, R. F., Kong, B., Demir, I. E., Friess, H., Rad, R., Saur, D., Schneider, G., and Reichert, M. (2022). EMBO Mol Med 14, e14876. doi: 10.15252/emmm.202114876
Kaltenbacher, T., Loprich, J., Maresch, R., Weber, J., Muller, S., Oellinger, R., Gross, N., Griger, J., de Andrade Kratzig, N., Avramopoulos, P., Ramanujam, D., Brummer, S., Widholz, S. A., Barthel, S., Falcomata, C., Pfaus, A., Alnatsha, A., Mayerle, J., Schmidt-Supprian, M., Reichert, M., Schneider, G., Ehmer, U., Braun, C. J., Saur, D., Engelhardt, S., and Rad, R. (2022). Nat Protoc 17, 1142-1188. doi: 10.1038/s41596-021-00677-0
Schneeweis, C., Hassan, Z., Ascherl, K., Wirth, M., Koutsouli, S., Orben, F., Krauss, L., Schneider, C., Ollinger, R., Kramer, O. H., Rad, R., Reichert, M., Robles, M. S., Saur, D., and Schneider, G. (2022). Cancer Commun (Lond) 42, 360-364. doi: 10.1002/cac2.12280