|PD Dr. Dirk Schmidt-Arras|
|Inflammation and Cancer|
Cancer is one of the leading causes of death worldwide. Very often patients present at advanced stages of disease with tumor cell dissemination at distant organ sites, a process called metastasis. For many tumor entities, an efficient curative therapy is still lacking.
Growth of normal tissue cells but also tumour cells is regulated by intercellular and intracellular communication. Cells of the microenvironment, including inflammatory cells such as myeloid cells and lymphocytes, but also stromal cells such as fibroblasts secrete cytokines that act as paracrine factors either promoting or inhibiting cellular growth (Figure 1). Cytokines are also major regulators of anti-tumour immunity and key molecules in tumour metastasis.
Our group is aiming to understand how signalling cues promote tumour growth and metastasis with ultimate goal to develop novel therapeutic strategies. To this end we're applying biochemical and cell biological methods, bioinformatics and different in vivo mouse models.
Figure 1: Cytokines secreted by cells of the tumour microenvironment determine anti-tumour immunity, tumour growth and metastasis.
Selectivity and spatio-temporal control of cytokine signalling
Figure 2: Overview of the IL-6 cytokine family that share the common signal transducing subunit GP130.
The family of IL-6 cytokines has eleven members and pleiotropic functions within the body. All family members share the same signal transducing subunit GP130 (Figure 2). In the recent years, gain- and loss-of-function mutations have been discovered in different pathologies, including liver cancer. On the basis of these mutations, we're trying to understand how GP130 signals emerge from different subcellular localisations (Figure 3 a), how they differ in signal quality and how cytokine selectivity of GP130 is achieved at a molecular level.
IL-6 family cytokines can have diverse biological outcomes depending on the cell type of the receiver cell (Figure 3 b). Current mouse models were unable to dissect cell type-specific cytokine effects. By using a novel in vivo mouse model we're now able to analyse cell type-specific effect of GP130 signals to a certain biological outcome in different pathological settings including primary tumour growth and metastasis. Based on our findings we aim to interfere with GP130 signalling in a cell type-specific manner.
Figure 3: The biological outcome of GP130 signals is determined by a) signal emission from different subcellular compartments and b) the cell type of the signal-receiving cell.
ADAM proteases in the tumour microenvironment
The family of ADAM (A disintegrin and metalloprotease) proteases has been implicated in a variety of signalling processes. Ectodomain shedding of cytokines like e.g. TNFα, growth-factors like e.g. TGFα and receptors like e.g. Notch have been shown to be mediated by ADAM10 and ADAM17. As such ADAM proteases have been implicated in a number of tumours. However, little is known about the role of ADAM proteases in the tumor stroma and cells of the metastatic niche. We're investigating how ADAM proteases in the tumour microenvironment regulates primary tumour growth and metastasis (Figure 4)
Figure 4: ADAM proteases on cells of the tumour microenvironment regulate primary tumour growth and different steps of tumour metastasis.Major contributions:
Letzte Änderung/Last change: Mai 28, 2021