Prof. Dr. Silvia von Karstedt

Research Area: Cell Death and Cancer Evolution

Branches: Cancer BiologyCell BiologyImmunology

1. Research Background

The evolution of cancer cells within tumours is tightly regulated by repeated cycles of cell proliferation, selection of the fittest cellular clone and cell death of all weaker clones. Thereby, cancers strictly follow a rule of "Darwinian" selection throughout their existence. Although the induction of cell death in a cancer cell is wanted from a therapeutic viewpoint and common cancer therapeutics therefore aim to trigger selective tumour cell death, this is also the driver behind selection for the most aggressive cancer cell clone causing therapy resistance and relapse. Even before selection through exposure to cell death-inducing therapy, tumours evolve to evade cell death induction through natural means of a bodies defense mechanisms, i.e. the immune system. Hence, developing resistance to cell death induction even before therapy is a hallmark of cancer enabling its growth. Thereby, unintentionally anti-cancer immune cells might contribute to the selection of the most aggressive cellular clone by creating constant selective pressure through cell death induction. The von Karstedt lab has previously shown that cancer cells expressing oncogenic KRAS are rendered resistant to ferroptosis (Müller et al. 2022) but are selectively sensitive to necroptosis, a highly inflammatory type of regulated necrosis (Tishina et al. 2023).

2. Research questions addressed by the group:

We are interested in understanding the role of evasion of different forms of cell death in cancer selection-of-the-fittest. In this context, projects in the lab activate necroptosis or ferroptosis genetically in mouse models of cancer including pancreatic ductal adenocarcinoma (PDAC), small cell lung cancer (SCLC) and diffuse large B-cell lymphoma (DLBCL) and trace cancer development and progression. We anticipate that unravelling mechanisms of selection-of-the-fittest in these cancers may contribute to identifying new target pathways to interfere with (early onset) carcinogenesis and eventually translate into novel therapeutic approaches to treat these patients.

3. Possible project(s):

We recently found that deletion of caspase 8 in PDAC leads to decreased tumour burden due to the induction of necroptosis. Mechanistically, we found that expression of oncogenic KRAS induces a type I interferon (IFN) response which leads to the upregulation of necroptosis pathway components and, hence, to necroptosis sensitisation (Tishina et al. 2023). In unpublished data, we found that the few lesions remaining after necroptosis induction present with profiles of ferroptosis sensitivity opening the possibility that targeting both pathways may be beneficial for the treatment of PDAC. To investigate this, the student will cross breed genetic models of PDAC to induce ferroptosis and necroptosis and perform detailed single cell level analysis of inflammatory processes within lesions. We anticipate that this investigation will identify novel combinatorial treatment options for PDAC, one of the most aggressive cancer entitites.

4. Applied Methods and model organisms:

The project described above is based around extensive in vivo work, including weighing, breeding, injecting and sacrificing mice for tissue harvest and subsequent analysis. Tissues will be analyzed using microscopy, histochemistry, FACS analysis, scRNA-seq. The project further includes standard wet-lab-work, such as mammalian cell culture, Western blotting and (rt)-PCR.

5. Desirable skills and qualifications:

The successful candidate will have excellent grades and a keen interest in cancer biology. He or she should be positive, curious and resilient. We are looking for an open minded and cooperative person, that is highly motivated and thrives in research projects within an international and competitive environment. Willingness to do mouse work is a prerequisite, and previous experience in in vivo work is desirable. Furthermore, experience in least some of the techniques mentioned above is required and an understanding of bioinformatic analysis desirable but not required.

6. References and key publications:

  1. Tishina, S. et al. Oncogenic KRAS-induces necroptotic priming of pancreatic neoplasia. (2023) doi:10.21203/
  2. Müller, F. et al. Elevated FSP1 protects KRAS-mutated cells from ferroptosis during tumor initiation. Cell Death Differ. 1–15 (2022) doi:10.1038/s41418-022-01096-8.
  3. Karstedt, S. von et al. Cancer cell-autonomous TRAIL-R signaling promotes KRAS-driven cancer progression, invasion, and metastasis. Cancer Cell 27, 561–573 (2015).
  4. Karstedt, S. von, Montinaro, A. & Walczak, H. Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nat. Publ. Group 17, 352–366 (2017).