Center for Molecular Medicine Cologne

von Karstedt, Silvia - A 07

Targeting the Necroptosis Pathway in Pancreatic Cancer

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is amongst the deadliest cancers with a 5-year survival rate of below 5%. This poor prognosis is caused by absence of specific early symptoms and primary resistance to chemotherapy highlighting an urgent need to improve our understanding of PDAC tumour biology.

One of the key features of PDAC is the high incidence (95%) of activating mutations in the proto-oncogene KRAS. Oncogenic KRAS is known to promote resistance against intrinsic and extrinsic apoptosis, two regulated types of cell death executed by enzymatic cascades initiated by caspase activation. Counterintuitively, we find that caspase 8 - an essential enzyme in the extrinsic apoptosis cascade - is upregulated in PDAC hinting at an unknown tumour-protective function. In fact, conditional deletion of caspase 8 within a genetically-engineered mouse model of KRASG12D-driven pancreatic intraepithelial neoplasia (PanINs) ameliorated disease progression supporting this hypothesis. As caspase 8 has been shown to protect cells from aberrant necroptotic cell death, here we propose to undertake work testing the hypothesis

  1. that caspase 8 deletion in pancreatic cancer triggers necroptosis
  2. how oncogenic KRAS signalling may influence necroptotic signalling and
  3. whether necroptosis induction in PDAC interacts with immunotherapy.

We thereby anticipate to identify cell death vulnerabilities in conjunction with potential markers during early PDAC progression for the development of novel treatment strategies.

Figure 1

Clinical relevance

PDAC patient outlook has not improved since the 1970ies. Thereby, PDAC is amongst the few cancers with an almost identical rate of incidence and mortality. This marks PDAC as one of the cancers with unmet needs warranting the urgent requirement for novel therapeutic strategies. Here, we propose to investigate PDAC cell death biology in in-vivo model systems in order to address this need. Therapeutic approaches identified will take clinically advanced compound combinations into consideration.

Approach

  • Use of KRAS-inducible cellular systems
  • Use of genetically engineered mouse models to study necroptosis in PanIN-to-PDAC-progression
  • Use of genetically engineered mouse models to test pharmacological induction of necroptosis in PDAC
Figure 2
  • Müller F, Lim JKM, Bebber CM, Seidel E, Tishina S, Dahlhaus A, Stroh J, Beck, J, Yapici FI, Nakayama K, Torres Fernández L,Brägelmann J, Leprivier G, von Karstedt S. 2022. Elevated FSP1 protects KRAS-mutated cells from ferroptosis during tumor initiation. Cell Death Differ 1–15 (2022) doi:10.1038/s41418-022-01096-8.
  • Bebber CM, Thomas ES, Stroh J, Chen Z, Androulidaki A, Schmitt A, Höhne MN, Stüker L, Alves C de P, Khonsari A, Dammert MA, Parmaksiz F, Tumbrink HL, Beleggia F, Sos ML, Riemer J, George J, Brodesser S, Thomas RK, Reinhardt HC, Karstedt S von. 2021. Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes. Nature Communications 12:2048–19.
  • Pedrera L, Espiritu RA, Ros U, Weber J, Schmitt A, Stroh J, Hailfinger S, Karstedt S von, García-Sáez AJ. 2020. Ferroptotic pores induce Ca 2+ fluxes and ESCRT-III activation to modulate cell death kinetics. Cell Death Differ 149:1–14.
  • Clemente LP, Rabenau M, Tang S, Stanka J, Cors E, Stroh J, Culmsee C, Karstedt S von. 2020. Dynasore Blocks Ferroptosis through Combined Modulation of Iron Uptake and Inhibition of Mitochondrial Respiration. Cells 9:2259.
  • Bebber, C. M., Müller, F., Prieto Clemente, L., Weber, J. & Karstedt, von, S. Ferroptosis in Cancer Cell Biology. Cancers (Basel) 12, 164 (2020).
  • Lim, J.K.M., Delaidelli, A., Minaker, S.W., Zhang, H.-F., Colovic, M., Yang, H., Negri, G.L., Karstedt, von, S., Lockwood, W.W., Schaffer, P., Leprivier, G., Sorensen PH. 2019. Cystine/glutamate antiporter xCT (SLC7A11) facilitates oncogenic RAS transformation by preserving intracellular redox balance. PNAS. U.S.A. 1092, 9433-9442.
  • von Karstedt, S.*, Montinaro, A.*, and Walczak, H. (2017). Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nat. Rev. Cancer17, 352–366.   *equal contribution
  • Hartwig, T.*, Montinaro, A.*, von Karstedt, S.*, Sevko, A., Surinova, S., Chakravarthy, A., Taraborrelli, L., Draber, P., Lafont, E., Arce Vargas, F., Bahrawy, M. A., Quezada, S. A., and Walczak, H. (2017). The TRAIL-induced cancer secretome promotes a tumor-supportive immune-microenvironment via CCR2. Mol. Cell65, 730–742.e5.   * equal contribution
  • von Karstedt, S., Conti, A., Nobis, M., Montinaro, A., Hartwig, T., Lemke, J., Legler, K., Annewanter, F., Campbell, A.D., Taraborrelli, L., Grosse-Wilde, A., Coy, J. F., El-Bahrawy, M. A., Bergmann, F., Koschny, R., Werner, J., Ganten, T. M., Schweiger, T., Hoetzenecker, K., Kenessey, I., Hegedüs, B., Bergmann, M., Hauser, C., Egberts, J.-H., Becker, T., Röcken, C., Kalthoff, H., Trauzold, A., Anderson, K. I., Sansom, O. J., and Walczak, H. (2015). Cancer Cell-Autonomous TRAIL-R Signaling Promotes KRAS-Driven Cancer Progression, Invasion, and Metastasis. Cancer Cell27, 561-573.
  • Lemke J., von Karstedt S., Abd El Hay M., Conti A., Arce F., Montinaro A., Papenfuss K., El-Bahrawy M. A., and Walczak, H. (2014). Selective CDK9 inhibition overcomes TRAIL resistance by concomitant suppression of cFlip and Mcl-1. Cell Death Differ. 21, 491-502.

Overview of publications generated during the current funding period (1/2023-12/2025) with CMMC affiliation

For a complete list of S. von Karstedt's publications, please visit - pubmed_von Karstedt

  • Muller F, Lim JKM, Bebber CM, Seidel E, Tishina S, Dahlhaus A, Stroh J, Beck J, Yapici FI, Nakayama K, Torres Fernandez L, Bragelmann J, Leprivier G, and von Karstedt S (2023). Elevated FSP1 protects KRAS-mutated cells from ferroptosis during tumor initiation. Cell Death Differ 30, 442-456. doi:10.1038/s41418-022-01096-8.
     
  • Vitale I, Pietrocola F, Guilbaud E, Aaronson SA, Abrams JM, Adam D, Agostini M, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Aqeilan RI, Arama E, Baehrecke EH, Balachandran S, Bano D, Barlev NA, Bartek J, Bazan NG, Becker C, Bernassola F, Bertrand MJM, Bianchi ME, Blagosklonny MV, Blander JM, Blandino G, Blomgren K, Borner C, Bortner CD, Bove P, Boya P, Brenner C, Broz P, Brunner T, Damgaard RB, Calin GA, Campanella M, Candi E, Carbone M, Carmona-Gutierrez D, Cecconi F, Chan FK, Chen GQ, Chen Q, Chen YH, Cheng EH, Chipuk JE, Cidlowski JA, Ciechanover A, Ciliberto G, Conrad M, Cubillos-Ruiz JR, Czabotar PE, D'Angiolella V, Daugaard M, Dawson TM, Dawson VL, De Maria R, De Strooper B, Debatin KM, Deberardinis RJ, Degterev A, Del Sal G, Deshmukh M, Di Virgilio F, Diederich M, Dixon SJ, Dynlacht BD, El-Deiry WS, Elrod JW, Engeland K, Fimia GM, Galassi C, Ganini C, Garcia-Saez AJ, Garg AD, Garrido C, Gavathiotis E, Gerlic M, Ghosh S, Green DR, Greene LA, Gronemeyer H, Hacker G, Hajnoczky G, Hardwick JM, Haupt Y, He S, Heery DM, Hengartner MO, Hetz C, Hildeman DA, Ichijo H, Inoue S, Jaattela M, Janic A, Joseph B, Jost PJ, Kanneganti TD, Karin M, Kashkar H, Kaufmann T, Kelly GL, Kepp O, Kimchi A, Kitsis RN, Klionsky DJ, Kluck R, Krysko DV, Kulms D, Kumar S, Lavandero S, Lavrik IN, Lemasters JJ, Liccardi G, Linkermann A, Lipton SA, Lockshin RA, Lopez-Otin C, Luedde T, MacFarlane M, Madeo F, Malorni W, Manic G, Mantovani R, Marchi S, Marine JC, Martin SJ, Martinou JC, Mastroberardino PG, Medema JP, Mehlen P, Meier P, Melino G, Melino S, Miao EA, Moll UM, Munoz-Pinedo C, Murphy DJ, Niklison-Chirou MV, Novelli F, Nunez G, Oberst A, Ofengeim D, Opferman JT, Oren M, Pagano M, Panaretakis T, Pasparakis M, Penninger JM, Pentimalli F, Pereira DM, Pervaiz S, Peter ME, Pinton P, Porta G, Prehn JHM, Puthalakath H, Rabinovich GA, Rajalingam K, Ravichandran KS, Rehm M, Ricci JE, Rizzuto R, Robinson N, Rodrigues CMP, Rotblat B, Rothlin CV, Rubinsztein DC, Rudel T, Rufini A, Ryan KM, Sarosiek KA, Sawa A, Sayan E, Schroder K, Scorrano L, Sesti F, Shao F, Shi Y, Sica GS, Silke J, Simon HU, Sistigu A, Stephanou A, Stockwell BR, Strapazzon F, Strasser A, Sun L, Sun E, Sun Q, Szabadkai G, Tait SWG, Tang D, Tavernarakis N, Troy CM, Turk B, Urbano N, Vandenabeele P, Vanden Berghe T, Vander Heiden MG, Vanderluit JL, Verkhratsky A, Villunger A, von Karstedt S, Voss AK, Vousden KH, Vucic D, Vuri D, Wagner EF, Walczak H, Wallach D, Wang R, Wang Y, Weber A, Wood W, Yamazaki T, Yang HT, Zakeri Z, Zawacka-Pankau JE, Zhang L, Zhang H, Zhivotovsky B, Zhou W, Piacentini M, Kroemer G, and Galluzzi L (2023). Apoptotic cell death in disease-Current understanding of the NCCD 2023. Cell Death Differ 30, 1097-1154. doi:10.1038/s41418-023-01153-w.
     
Prof. Dr. Silvia von Karstedt CMMC Cologne
Prof. Dr. Silvia von Karstedt

Department of Translational Genomics | CECAD Research Center

CMMC - PI - A 07

+49 221 478 84340

Department of Translational Genomics | CECAD Research Center

Joseph-Stelzmann-Str. 26

50931 Cologne

https://www.translational-genomics.de/research-groups/von-karstedt-lab

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