Research Area: Death Receptors and Inflammation in Cancer
Cell death is a vital process occurring every day in the human body. Many processes such as maintenance of tissue homeostasis, support in recovery from acute injury as well as dealing with infections and regulation of the immune system rely on proper cell death function. In addition, cell death can also provoke inflammatory responses, and lytic forms of cell death can incite inflammation by promoting the production of cytokines and chemokines that modulate the innate immune response. Cell death can be both a consequence and a cause of inflammation, which can be difficult to distinguish. In the past decade, emerging knowledge on the interplay between cell death and inflammation has enriched the molecular understanding of the signaling pathways that mediate various programmes of cell death and multiple types of inflammatory responses. Strikingly, dysregulation of cell death or inflammation can lead to severe diseases, including autoimmune or degenerative disorders and cancer. It is therefore important to characterise the molecules and pathways that modulate cell death and inflammation to identify new therapeutic means to effectively treat such diseases.
Members of the tumor necrosis factor (TNF) family, e.g. TNF itself but also FasL and TRAIL, have previously been shown by us and others to induce inflammation as a consequence of cell death. By binding to their respective receptors which are located on the plasma membrane, these so-called death ligands activate these receptors which cannot only elicit the induction of cell death but also of gene expression which can also induce inflammation. We identified the intracellular multi-protein complex LUBAC as a component essential for regulating the signalling output of all different receptors for these death ligands. Importantly, this especially applies to the balance between cell death and gene-activatory signalling and how a deregulation of this balance can result in inflammatory disease. Additionally, we discovered that in cancer different death receptors, especially TRAIL receptors, rather than serving as cancer suppressors, which one could have assumed to be the consequence of their cell death-inducing capacity, act in a tumour-supportive manner.
Research in the Walczak Laboratory is focused on cell death and ubiquitin in inflammation, cancer and immunity. The lab is particularly interested in unravelling the mechanisms on how different death receptor-ligand systems, especially the TNF–TNFR, Fas–FasL and TRAIL–TRAIL-R systems, are regulated and how they impact cancer cell survival and metastasis as well as cancer-related inflammation and tumour immunity. The overarching aim of the Walczak group is to gain a deeper understanding of the interplay between cell death and inflammation and, on the basis thereof, provide novel therapies by therapeutic targeting of the perturbed physiological balance between cell death and inflammation which underlies many of the pathologies cited above, including cancer.
More than twenty percent of all human cancers bear oncogenic mutations in KRAS. Cancer driven by most forms of KRAS remain difficult to treat. Many effector pathways downstream of KRAS have been implicated in KRAS-driven tumour development and maintenance and, consequently, small molecule inhibitors targeting these pathways have been developed. Yet, clinical application of these drugs has revealed resistance-causing feedback mechanisms for virtually all of them.
TNF-related apoptosis-inducing ligand receptor (TRAIL-R) is a member of the TNF receptor superfamily and has mostly been studied for its induction of cell death. The findings that its ligand, TRAIL, can selectively kill tumor cells without toxicity against normal tissues in vivo led to the development of TRAIL-R agonists for cancer therapy. However, many tumour cell lines and primary tumours are resistant to TRAIL-induced apoptosis.Yet, many cancer cells retain high TRAIL-R expression and in a cancer metastasis model therapeutic administration of TRAIL promoted liver metastasis of KRAS-mutated colorectal cancer cells in vivo. These observations raise the fundamental question how cancers benefit from signalling via the TRAIL–TRAIL-R system.
In this regard, we first discovered that TRAIL–TRAIL-R signalling promotes KRAS-driven cancer migration, invasion and metastasis in the absence of apoptosis induction. These results highlighted an important aspect of cancer biology, namely that cancer cells can turn “cell death pathways” into tumour-promoting “survival and migration pathways”. We found the membrane-proximal domain of TRAIL-R to be required for activation of Rac1, a Rho family GTPase, a well-known driver of migration, invasion and metastasis thought to be activated by mutated KRAS. We, however, found that in the absence of endogenous TRAIL-R, KRAS was not sufficient to activate Rac1 and to drive cancer progression and metastasis. These results suggested that the inhibition of TRAIL could serve as a treatment for KRAS-mutated cancers.
In addition, we discovered that TRAIL can also activate survival and proliferation pathways in cancer cells such as those mediated via nuclear factor-κB (NF-κB), the mitogen-activated kinases (MAPKs) JNK, p38, and ERK, as well as the kinase Src and that these TRAIL-induced signalling outputs, which we discovered require LUBAC, act pro-tumourigenically in a TRAIL-R death domain-dependent manner. Therefore, we have identified two independent but likely synergistic ways in which the TRAIL – TRAIL-R system can support tumours.
However, several key questions that are intimately related to these recent discoveries by the Walczak lab remain unanswered:
By unravelling the biochemical, functional and (patho-)physiological differences between different death receptors the proposed project aims at unveiling new therapeutic avenues for more effective future treatment of both, KRAS-driven and non-KRAS-driven cancers.
Flow and mass cytometry, cell culture, immunoprecipitation, western blotting, mass spectrometry, in-vivo work with different mouse tumour models, bulk and single cell RNAseq, qPCR, ELISA