Project P04
Functional characterization of the atypical member of the IkappaB inhibitor Bcl-3 in pancreatic ductal adenocarcinoma
Comprehensive Cancer Center München des Klinikums rechts der Isar, Technical University of Munich
hana.alguel@mri.tum.de(link sends e-mail)
Homepage(link is external)
As mostly ubiquitously expressed transcription factors, proteins of the NF-kappaB family can control the growth and malignancy of many solid tumors, including pancreatic cancer, via the regulation of expression of a large number of downstream genes that control cell proliferation, survival, stress and immune responses. The full importance of NF-kappaB and STAT3 signaling to cancer development and maintenance has been shown. However, despite extensive characterization of NF-kappaB and STAT3 signaling, the specific functional roles of different members of the NF-kappaB and STAT3 family and their interaction in pancreatic cancer are not completely understood.
B-cell CLL/lymphoma 3 (BCL-3), an atypical member of the Inhibitor of kappa-B (IkappaB) family of proteins, is an established oncogene in hematologic malignancies. It predominantly resides in the nucleus and is not degraded upon NF-kappaB activation. Still, the functional outcome of interaction between BCL-3 and NF-kappaB has been controversial. Specific residues of BCL-3 have been shown to require phosphorylation through AKT, ERK2 and IKK1/2 to act as a transcriptional co-regulator of NF-kappaB.
Aiming to determine the role of BCL-3 in pancreatic cancer, we demonstrate overexpression and hyperphosphorylation of BCL-3 in human and murine PDAC tissues and cell lines. Using various in vivo and in vitro genetic tools our preliminary data reveal that BCL-3 is a novel tumor suppressor, negatively regulating the critical proinflammatory pathway STAT3 and metastasis by averting epithelial-mesenchymal transition. These data altogether indicate an important and previously unrecognized role for BCL-3 in PDAC metastasis, highlight several new aspects of BCL-3 in this disease. Therefore, through the generation of phosphorylation-sites specific mutants we plan to detail the tumor suppressor function of BCL-3 in PDAC and metastasis. Finally, the role of these specific residues of BCL-3 and their interaction with the STAT3 pathway will be investigated.
With all these analysis we aim to determine how this knowledge could be exploited for clinical applications.
Publications
Zhang, Z., Li, H., Deng, Y., Schuck, K., Raulefs, S., Maeritz, N., Yu, Y., Hechler, T., Pahl, A., Fernandez-Saiz, V., Wan, Y., Wang, G., Engleitner, T., Ollinger, R., Rad, R., Reichert, M., Diakopoulos, K. N., Weber, V., Li, J., Shen, S., Zou, X., Kleeff, J., Mihaljevic, A., Michalski, C. W., Algul, H., Friess, H., and Kong, B. (2021). Gastroenterology 161, 1601-1614 e1623. doi: 10.1053/j.gastro.2021.07.030
A Pancreas-Specific Ptf1a-Driven Cre Mouse Line Causes Paternally Transmitted Germline Recombination
Kabacaoglu, D., Ruess, D. A., Gorgulu, K., Steiger, K., Lesina, M., and Algul, H. (2021). Gastroenterology 161, 1695-1697 e169. doi: 10.1053/j.gastro.2021.06.050
Gorgulu, K., Kabacaoglu, D., and Algul, H. (2021). Signal Transduct Target Ther 6, 348. doi: 10.1038/s41392-021-00757-3
Ai, J., Wormann, S. M., Gorgulu, K., Vallespinos, M., Zagorac, S., Alcala, S., Wu, N., Kabacaoglu, D., Berninger, A., Navarro, D., Kaya-Aksoy, E., Ruess, D. A., Ciecielski, K. J., Kowalska, M., Demir, I. E., Ceyhan, G. O., Heid, I., Braren, R., Riemann, M., Schreiner, S., Hofmann, S., Kutschke, M., Jastroch, M., Slotta-Huspenina, J., Muckenhuber, A., Schlitter, A. M., Schmid, R. M., Steiger, K., Diakopoulos, K. N., Lesina, M., Sainz, B., Jr., and Algul, H. (2021). Gastroenterology 161, 318-332 e319. doi: 10.1053/j.gastro.2021.03.051
Liotta, L., Lange, S., Maurer, H. C., Olive, K. P., Braren, R., Pfarr, N., Muckenhuber, A., Jesinghaus, M., Weichert, W., Steiger, K., Burger, S., Friess, H., Schmid, R. M., Alguel, H., Jost, P., Ramser, J., Fischer, C., Quante, A. S., Reichert, M., and Quante, M. (2021). JCI Insight 6. doi: 10.1172/jci.insight.141532
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
Demir, I. E., Reyes, C. M., Alrawashdeh, W., Ceyhan, G. O., Deborde, S., Friess, H., Gorgulu, K., Istvanffy, R., Jungwirth, D., Kuner, R., Maryanovich, M., Na'ara, S., Renders, S., Saloman, J. L., Scheff, N. N., Steenfadt, H., Stupakov, P., Thiel, V., Verma, D., Yilmaz, B. S., White, R. A., Wang, T. C., Wong, R. J., Frenette, P. S., Gil, Z., and Davis, B. M. (2020). Cancer Cell 38, 11-14. doi: 10.1016/j.ccell.2020.05.023
Gorgulu, K., Diakopoulos, K. N., Kaya-Aksoy, E., Ciecielski, K. J., Ai, J., Lesina, M., and Algul, H. (2020). Cells 9. doi: 10.3390/cells9041063
Kabacaoglu, D., Ruess, D. A., Ai, J., and Algul, H. (2019). Cancers (Basel) 11. doi: 10.3390/cancers11070937
Golan, T., Hammel, P., Reni, M., Van Cutsem, E., Macarulla, T., Hall, M. J., Park, J. O., Hochhauser, D., Arnold, D., Oh, D. Y., Reinacher-Schick, A., Tortora, G., Algul, H., O'Reilly, E. M., McGuinness, D., Cui, K. Y., Schlienger, K., Locker, G. Y., and Kindler, H. L. (2019). N Engl J Med 381, 317-327. doi: 10.1056/NEJMoa1903387