Altered signalling pathways in B-cell lymphomas

The constitutive activation of different signalling pathways is essential for the pathobiology of B-cell lymphomas. This activation can be caused by external factors - such as cytokines or growth factors secreted by tumour-infiltrating lymphocytes - as well as intrinsic factors - such as hotspot mutations in oncogenes or inactivating mutations in tumour suppressor genes. Our research on B-cell lymphomas focuses on two main signalling cascades: The JAK/STAT (Janus kinase/signal transducer and activator of transcription) cascade and the NF-κB cascade.

When analysing the JAK/STAT signalling pathway, we are interested in two negative regulators of this cascade - SOCS1 (Suppressor of Cytokine Signaling 1) and PTP1B (Protein Tyrosine Phosphatase 1B). The analyses focus not only on the significance of the intact PTP1B and SOCS1 proteins, but above all on the potential role of mutated variants of these negative JAK/STAT regulators, as both tumour suppressor genes are frequently mutated in various types of B-cell lymphoma. We have already shown in the past that different variants of PTP1B, which lack individual exon regions, not only result in a loss of the negative PTP1B effect, but also have an oncogenic effect. In addition to an enhancing effect on the JAK/STAT signalling pathway, this also includes a positive influence on the survival and growth of Hodgkin's B-cell lymphoma cell lines.

The analysis of the NF-κB signalling pathways in B-cell lymphomas is the second focus of this research area. Here we are concentrating specifically on the significance and regulation of the signalling-induced degradation of the NF-κB transcription factor RelB. RelB can exert a positive function as part of the so-called alternative NF-κB signalling pathway as well as negatively influence NF-κB-dependent gene expression as part of an epigenetic regulatory mechanism. In quiescent T and B cells, RelB has the role of suppressing the expression of important T and B cell-associated genes. However, this negative RelB-mediated gene expression block is eliminated in the course of antigen receptor activation in lymphoid cells by the regulated degradation of RelB. Interestingly, this degradation occurs constitutively in some B-cell lymphomas (e.g. DLBCL of the ABC type) and represents an important pathomechanism that is essential for the survival and growth of lymphoma cells. The significance and regulation of this pathomechanism is therefore at the centre of our research.

Project team:

Prof Dr Peter Möller
Prof Dr Ralf Marienfeld
Dr Malena Zahn
Julia Wildfeuer

Tumour heterogeneity in lung cancer

Lung cancer is not only one of the most common types of cancer, but also leads to death in a particularly high number of cases. It is divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), and the latter in turn into squamous cell carcinoma, adenocarcinoma and large cell lung carcinoma. Due to its aggressiveness, however, this type of cancer is also one of the best characterised. Knowledge of a whole series of driver mutations that are essential for the survival and growth of lung cancer cells led relatively early on to the development of drugs that enter the tumour cells as "small molecule inhibitors" and inhibit specific mutated proteins there, thus serving as the basis for targeted therapy. These include, for example, EGFR inhibitors and ALK inhibitors, which are used in the presence of specific EGFR mutations or ALK gene rearrangements. In addition to targeted therapies, immune checkpoint inhibitor (ICI) therapies have also recently been used successfully in treatment. ICIs are antibodies that break a receptor-ligand bond between tumour and immune cells, which form the basis for the "immune escape" of the tumour. Thus, the expression of the surface marker PD-L1 inhibits the activity of the T-cells through interaction with the receptor PD-1 expressed on T-cells and thus the elimination of the tumour cells. However, the success of both targeted therapies and ICI therapies is jeopardised by tumour heterogeneity in lung cancer. For example, additional mutations lead to the development of resistance in targeted therapies and to therapy failure. The analysis of tumour heterogeneity and its effects on the success of therapy in NSCLC are the focus of our research interest. By analysing RNA and DNA sequencing data from therapy-resistant NSCLC cases, new and better prediction tools will be developed. In addition, we are investigating how the expression of immune checkpoint proteins is regulated in tumour cells. We are also involved in the nNGM consortium and the LuCaBio registry study.

Project team:

Prof Dr Ralf Marienfeld
Stefanie Mayer
Tobias Kolb
Adna Karic
Prof Dr Thomas Barth