Center for Molecular Medicine Cologne

Silvia von Karstedt - A 06

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

Project Related Publications

  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.

Publications 2020

An unexpected turn of fortune: targeting TRAIL-Rs in KRAS-driven cancer.
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.

Dr. Silvia von Karstedt CMMC Cologne
Dr. Silvia von Karstedt

Department for Translational Genomics

CMMC - Principal Investigator - A 06

+49 221 478 84340

Department for Translational Genomics

CECAD Research Center University of Cologne Joseph-Stelzmann-Str. 26

50931 Cologne

http://vonkarstedt.cecad-labs.de/Home.824.0.html

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Curriculum Vitae (CV)

Publications on PubMed

Publications - Silvia von Karstedt

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Figure 1
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)