Project P05
Dissecting Toll-like receptor 3 function in pancreatic regeneration and neoplastic transformation

bernhard.holzmann@tum.de(link sends e-mail)
Homepage(link is external)
The innate immune system has an important role in initiation and progression of pancreatic ductal adenocarcinoma (PDAC). The Toll-like receptor (TLR) pathways, major determinates of innate immunity, are frequently altered at the genetic level in PDAC. In particular, components of the TLR3 pathway are affectedmutated in about 40% of pancreatic cancers and are associated with reduced survival. However, the functional role of this pathway in pancreatic tumorigenesis is poorly understood.
Our own preliminary work shows pronounced formation and persistence of acinar to ductal metaplasia (ADM) and inflammation upon pancreatitis induction in mice generally lacking TLR3. In contrast, myeloid specific reconstitution of TLR3 in mice lacking TLR3 partially rescues regenerative capacity. In the context of oncogenic Kras signaling, loss of non-epithelial TLR3 induces a marked inflammatory response and accelerates formation of PDAC precursors. Based on these results we hypothesize that the nucleic acid sensor TLR3 plays an essential and compartment-specific role during regeneration and carcinogenesis in the pancreas.
In this research initiative, we aim to dissect the specific role of TLR3 in pancreatic regeneration and cancer development making use of a novel mouse model that allows for independent and cell-specific expression of both oncogenic Kras and TLR3. Findings from mouse models will be validated for human relevance by analysis of TLR3-deficient human organoids and cell lines and association of TLR3-deficiency with therapeutic traits. The overall aim is to identify new druggable pathways that critically influence pancreatic tumorigenesis.
Publications
Kidger, A. M., Saville, M. K., Rushworth, L. K., Davidson, J., Stellzig, J., Ono, M., Kuebelsbeck, L. A., Janssen, K. P., Holzmann, B., Morton, J. P., Sansom, O. J., Caunt, C. J., and Keyse, S. M. (2022). Oncogene 41, 2811-2823. doi: 10.1038/s41388-022-02302-0
Hidalgo-Sastre, A., Kuebelsbeck, L. A., Jochheim, L. S., Staufer, L. M., Altmayr, F., Johannes, W., Steiger, K., Ronderos, M., Hartmann, D., Huser, N., Schmid, R. M., Holzmann, B., and von Figura, G. (2021). Eur J Immunol 51, 1182-1194. doi: 10.1002/eji.202048771
Dantes, Z., Yen, H. Y., Pfarr, N., Winter, C., Steiger, K., Muckenhuber, A., Hennig, A., Lange, S., Engleitner, T., Ollinger, R., Maresch, R., Orben, F., Heid, I., Kaissis, G. A., Shi, K., Topping, G. J., Stogbauer, F., Wirth, M., Peschke, K., Papargyriou, A., Rezaee-Oghazi, M., Feldmann, K., Schafer, A. P. G., Ranjan, R., Lubeseder-Martellato, C., Stange, D. E., Welsch, T., Martignoni, M. E., Ceyhan, G. O., Friess, H., Herner, A., Liotta, L., Treiber, M., von Figura, G., Abdelhafez, M., Klare, P., Schlag, C., Algul, H., Siveke, J. T., Braren, R. F., Weirich, G., Weichert, W., Saur, D., Rad, R., Schmid, R., Schneider, G., and Reichert, M. (2020). JCI Insight 5. doi: 10.1172/jci.insight.137809
Hidalgo-Sastre, A., Lubeseder-Martellato, C., Engleitner, T., Steiger, K., Zhong, S., Desztics, J., Ollinger, R., Rad, R., Schmid, R. M., Hermeking, H., Siveke, J. T., and von Figura, G. (2020). Sci Rep 10, 9654. doi: 10.1038/s41598-020-66561-1
Hidalgo-Sastre, A., Desztics, J., Dantes, Z., Schulte, K., Ensarioglu, H. K., Bassey-Archibong, B., Ollinger, R., Engleiter, T., Rayner, L., Einwachter, H., Daniel, J. M., Altaee, A. S. A., Steiger, K., Lesina, M., Rad, R., Reichert, M., von Figura, G., Siveke, J. T., Schmid, R. M., and Lubeseder-Martellato, C. (2020). JCI Insight 5. doi: 10.1172/jci.insight.127275
Jochheim, L. S., Odysseos, G., Hidalgo-Sastre, A., Zhong, S., Staufer, L. M., Kroiss, M., Kabacaoglu, D., Lange, S., Engleitner, T., Hartmann, D., Huser, N., Steiger, K., Schmid, R. M., Holzmann, B., and von Figura, G. (2019). Pancreatology : official journal of the International Association of Pancreatology (IAP) [et al] 19, 541-547. doi: 10.1016/j.pan.2019.05.455