Center for Molecular Medicine Cologne

von Karstedt, Silvia - A 06

Elucidation of ferroptosis-inducing therapy (FIT) for the treatment of pancreatic cancer


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 address these two problems. Molecularly, PDAC is characterised by the presence of activating point mutation in the small GTPase KRAS in 95% of the cases. This point mutation leads to constitutive activation of KRAS, promoting proliferation, invasion and cell death resistance. We recently contributed to a study identifying that the cystine/glutamate antiporter xCT (SLC7A11) promotes Ras-mediated transformation by protecting cells from reactive oxygen species (ROS) overload (Lim et al., 2019). Interestingly, xCT has been implicated in the protection against a recently discovered form of regulated necrosis, termed ferroptosis. Sensitivity to ferroptosis, in turn, has emerged as a selective vulnerability in cancer cells which escape targeted treatment. Based on these findings, we have experimentally explored whether the KRASG12D mutation which is prevalent in PDAC might be promoting malignancy through evading ferroptosis. The aim of this project to establish i) whether ferroptosis evasion might determine KRASG12D fitness in PDAC development ii) and how breaking ferroptosis evasion might affect the development of PDAC precursor lesions in a genetically-engineered mouse model. We thereby anticipate to identify cell death vulnerabilities in conjunction with potential markers during early PDAC progression for the development of novel treatment strategies. 

Clinical relevance

The poor 5-year survival rate of below 5% of PDAC patients has not significantly improved since the 1970ies. This has marked PDAC as one of the cancers with unmet needs warranting the urgent requirement to explore novel therapeutic strategies. We propose to test ferroptosis-inducing therapy (FIT) in in-vitro and in-vivo PDAC model systems in order to address this need. Findings made in these model systems will be corroborated in a PDAC patient tissue bank.

Our Aims

  1. Elucidate mechanisms of ferroptosis response in KRAS-mutated cells
    • Define proteomics of KRAS mutated and wild type cells upon induction of ferroptosis
    • Define expression changes of KRAS mutated and wild type cells upon induction of ferroptosis
    • Identify differential adaptation mechanisms in KRAS-mutated PDAC upon ferroptosis
    • Validation of role of differentially regulated factors
  2. Elucidate the role of genetic ferroptosis induction in the development and progression of PDAC
    • Determine the role of ferroptosis in PDAC development in vivo
    • Test FIT in KRAS-driven genetically engineered mouse models
    • Validation of expression of ferroptosis pathway components and potential prognostic value in a patient biobank

Previous Work

Most tumours are known to undergo constant cycles of selection via immune effector cells. One pathway via which immune effector cells kill target cells is extrinsic apoptosis induction via ligand/receptor binding of Tumor necrosis factor (TNF)- and TNF-receptor (TNFR) superfamily (SF) members (Karstedt et al., 2017). Yet, given the fast kinetics and efficiency by which extrinsic apoptosis can eliminate targeted cells, it is not surprising that tumours frequently develop escape mechanisms against extrinsic apoptosis. In KRAS-driven PDAC, we previously found that extrinsic apoptosis is disabled (Karstedt et al., 2015). Interestingly, Ferroptosis is a recently discovered type of regulated necrosis which, unlike apoptosis, is independent of caspase. Instead, ferroptotic cells die following iron-dependent lipid peroxidation, a process which is antagonised by glutathione peroxidase 4 (GPX4), by the cystine/glutamate antiporter xCT (SLC7A11) and ferroptosis suppressor protein 1 (FSP1) (reviewed in Bebber et al. under review). Importantly, tumour cells escaping other forms of regulated cell death maintain or acquire sensitivity to ferroptosis (Thomas*, Bebber* et al. in preparation). As part of this project, it will be tested whether KRAS-mutated PDAC which is resistant to extrinsic apoptosis can respond to ferroptosis-inducing therapy (FIT). Findings made unbiased studies will be validated mechanistically and tested in genetically engineered mouse models for PDAC. 

  1. Karstedt, von, S., Conti, A., Nobis, M., Montinaro, A., Hartwig, T., Lemke, J., Legler, K., Annewanter, F., Campbell, A.D., Taraborrelli, L., et al. (2015). Cancer cell-autonomous TRAIL-R signaling promotes KRAS-driven cancer progression, invasion, and metastasis. Cancer Cell 27, 561–573.
  2. Karstedt, von, S., Montinaro, A., and Walczak, H. (2017). Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nature Publishing Group 17, 352–366.
  3. 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., et al. (2019). Cystine/glutamate antiporter xCT (SLC7A11) facilitates oncogenic RAS transformation by preserving intracellular redox balance. Proc. Natl. Acad. Sci. U.S.a. 1092, 201821323.
  • Bebber CM, Thomas ES, Stroh J, Chen Z, Androulidaki A, Schmitt A, Hohne MN, Stuker L, de Padua Alves C, Khonsari A, Dammert MA, Parmaksiz F, Tumbrink HL, Beleggia F, Sos ML, Riemer J, George J, Brodesser S, Thomas RK, Reinhardt HC, and von Karstedt S (2021). Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes. Nat Commun12, 2048. doi:10.1038/s41467-021-22336-4.
                          • Bragelmann J, Lorenz C, Borchmann S, Nishii K, Wegner J, Meder L, Ostendorp J, Ast DF, Heimsoeth A, Nakasuka T, Hirabae A, Okawa S, Dammert MA, Plenker D, Klein S, Lohneis P, Gu J, Godfrey LK, Forster J, Trajkovic-Arsic M, Zillinger T, Haarmann M, Quaas A, Lennartz S, Schmiel M, D'Rozario J, Thomas ES, Li H, Schmitt CA, George J, Thomas RK, von Karstedt S, Hartmann G, Buttner R, Ullrich RT, Siveke JT, Ohashi K, Schlee M, and Sos ML (2021). MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I. Nat Commun12, 5505. doi:10.1038/s41467-021-25728-8.
                                                                                                                                                                                                                                                  • Montinaro A, Areso Zubiaur I, Saggau J, Kretz AL, Ferreira RMM, Hassan O, Kitzig E, Muller I, El-Bahrawy MA, von Karstedt S, Kulms D, Liccardi G, Lemke J, and Walczak H (2021). Potent pro-apoptotic combination therapy is highly effective in a broad range of cancers. Cell Death Differ. doi:10.1038/s41418-021-00869-x.
                                                                                                                                                                                                                                                                              • Pedrera L, Espiritu RA, Ros U, Weber J, Schmitt A, Stroh J, Hailfinger S, von Karstedt S, and Garcia-Saez AJ (2021). Ferroptotic pores induce Ca(2+) fluxes and ESCRT-III activation to modulate cell death kinetics. Cell Death Differ28, 1644-1657. doi:10.1038/s41418-020-00691-x.
                                                                                                                                                                                                                                                                                                                                                                                                                          • Willms A, Schupp H, Poelker M, Adawy A, Debus JF, Hartwig T, Krichel T, Fritsch J, Singh S, Walczak H, von Karstedt S, Schafer H, and Trauzold A (2021). TRAIL-receptor 2-a novel negative regulator of p53. Cell Death Dis12, 757. doi:10.1038/s41419-021-04048-1.
                                                                                                                                                                                                                                                                                                                                                                                                                          • von Karstedt S, Walczak H.: An unexpected turn of fortune: targeting TRAIL-Rs in KRAS-driven cancer.Cell Death Discov. 2020 Mar 17;6:14. doi: 10.1038/s41420-020-0249-4. eCollection 2020. PMID: 32194994 Free PMC article. Review.
                                                                                                                                                                                                                                                                                                                                                                                                                          • Allgöwer C, Kretz AL, von Karstedt S, Wittau M, Henne-Bruns D, Lemke J. Cancers (Basel).: Friend or Foe: S100 Proteins in Cancer. 2020 Jul 24;12(8):2037. doi: 10.3390/cancers12082037. PMID: 32722137 Free PMC article. Review.
                                                                                                                                                                                                                                                                                                                                                                                                                          • Clemente LP, Rabenau M, Tang S, Stanka J, Cors E, Stroh J, Culmsee C, and von Karstedt S (2020). Dynasore Blocks Ferroptosis through Combined Modulation of Iron Uptake and Inhibition of Mitochondrial Respiration. Cells 9.
                                                                                                                                                                                                                                                                                                                                                                                                                          Prof. Dr. Silvia von Karstedt CMMC Cologne
                                                                                                                                                                                                                                                                                                                                                                                                                          Prof. Dr. Silvia von Karstedt

                                                                                                                                                                                                                                                                                                                                                                                                                          Department of Translational Genomics - CECAD Research Center

                                                                                                                                                                                                                                                                                                                                                                                                                          CMMC - PI - A 06

                                                                                                                                                                                                                                                                                                                                                                                                                          +49 221 478 84340

                                                                                                                                                                                                                                                                                                                                                                                                                          Department of Translational Genomics - CECAD Research Center

                                                                                                                                                                                                                                                                                                                                                                                                                          Joseph-Stelzmann-Str. 26

                                                                                                                                                                                                                                                                                                                                                                                                                          50931 Cologne


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                                                                                                                                                                                                                                                                                                                                                                                                                          Publications on PubMed

                                                                                                                                                                                                                                                                                                                                                                                                                          Publications - Silvia von Karstedt

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                                                                                                                                                                                                                                                                                                                                                                                                                          Group Members

                                                                                                                                                                                                                                                                                                                                                                                                                          Ariadne Androulidaki, PostDoc
                                                                                                                                                                                                                                                                                                                                                                                                                          Eric Seidel, PostDoc
                                                                                                                                                                                                                                                                                                                                                                                                                          Erica Benard, PostDoc
                                                                                                                                                                                                                                                                                                                                                                                                                          Christina Bebber, PhD Student
                                                                                                                                                                                                                                                                                                                                                                                                                          Fabienne Müller, PhD Student
                                                                                                                                                                                                                                                                                                                                                                                                                          Madhuri Puvvada, PhD Student
                                                                                                                                                                                                                                                                                                                                                                                                                          Sofya Tishina, PhD Student
                                                                                                                                                                                                                                                                                                                                                                                                                          Fatma Isil Yapici, PhD Student
                                                                                                                                                                                                                                                                                                                                                                                                                          Jenny Stroh, Technician