Dr. Silvia von Karstedt

Research Area: Cell death and cancer evolution

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

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. To kill tumour cells, immune effector cells can make use of tumor necrosis factor (TNF) superfamily ligands such as TNF, CD95L and TNF-related apoptosis-inducing ligand (TRAIL).

2. Research questions addresses by the group:

The von Karstedt lab investigates the function of different modes of cell death in

  • The selection of the fittest mutant KRAS clone in non-small cell lung cancer (NSCLC)
  • Influencing progression of premalignant KRAS-driven pancreatic lesions
  • The development and treatment of small cell lung cancer (SCLC)

By unravelling mechanisms of selection-of-the-fittest in lung and pancreatic cancer, we anticipate to identify pathways which select for (NSCLC, pancreatic cancer) or against (SCLC) driver mutations and at the same time to find new therapeutic vulnerabilities to treat these cancers.

3. Possible projects:

In recent years, immunotherapy utilising blockade of programmed death-1 (PD-1) or its ligand (PD-L1) has changed the face of cancer therapy dramatically. However, only about 20% of solid tumours with pre-existing tumour neoantigen -specific cytotoxic T-lymphocytes (CTLs) respond. Lung cancer harbours a high mutation rate which is known to favour response to immunotherapy. However, despite improved overall survival in non-small cell lung cancer (NSCLC) patients, only 12% of patients treated with an anti-PD1 antibody showed a 2-year progression-free survival. Interestingly, molecules belonging to the TNF superfamily are known effector molecules expressed by anti-tumour immune cells which are also employed in constitutive anti-tumour defence. Thereby, tumours with immunogenic properties likely undergo rounds of selection to become resistant against cell death pathways triggered by TNF superfamily ligands. These cell death pathways can include extrinsic apoptosis and necroptosis. The first being a cell death widely considered to be less inflammatory than the latter. Of note, a higher degree of inflammation during cell death is known to yield a higher chance of generating a systemic anti-tumour immune response. Therefore, tipping the balance towards a more inflammatory type of cell death during immunoediting or therapy is a desirable outcome in the treatment of cancer. Importantly, it is unknown which of these two cell death pathways is induced by anti-tumour T-cells under normal conditions or under checkpoint blockade such as anti-PD-1 treatment. Hence, this project will elucidate cell death pathway choices and their consequence for systemic immunity in NSCLC.

4. Applied Methods and model organisms:

Working on the project described above will involve standard mammalian cell culture with human and murine NSCLC cell lines, cell biological assays including cell viabiltiy, FACS, SDS-PAGE and Western Blotting, ELISA, BSA, RNAi, CRISPR-Cas9-mediated knockout, transient protein expression, generation of stable lines. Moreover, for plasmid generation cloning migth be required, bacterial plasmid amplification (Miniprep/Maxiprep). Importantly, this project will have a strong in-vivo part, so work will involve handling and working with mice (weighing, breeding, injecting) as well as using tissues coming from mice for further analysis (immunofluorescence and -histochemistry, dissociation and FACS, RNA-Seq from cells).

5. Desirable skills and qualifications:

The successful candidate should have excellent marks, be highly motivated, have a keen interest in cancer biology and have an open mind for working in an internationally competitive research team. Furthermore, technical experience in at least some of the cell biological techniques mentioned above are required. Willingness to work with mice is a requirement, experience with mousework desirable.

6. References:

  • von Karstedt, S.*, Montinaro, A.*, and Walczak, H. (2017). Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nature Reviews Cancer 2017, 352-366.   
  • von Karstedt, S., Conti, A., Nobis, M., Montinaro, A., Hartwig, T., Lemke, J., Legler, K., Annewanter, F., Campbell, A.D., Taraborrelli, L., et al. Cancer Cell-Autonomous TRAIL-R Signaling Promotes KRAS-Driven Cancer Progression, Invasion, and Metastasis. Cancer Cell 2015; 27:561-573.
  • 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.. The TRAIL-induced cancer secretome promotes a tumor-supportive immune-microenvironment via CCR2. Molecular Cell 2017 65, 730-742.e5.

* equal contribution