In order to maintain healthy tissue homeostasis, normal cells must proliferate if needed but also die when asked. Typically, during ageing, this process is slowed down but individual cells have had a lifetime to accumulate faulty DNA increasing their risk to become malignant. Malignant cancer cells within a tumour go on to evolve to avoid healthy tissue regulation resulting in constantly proliferating cancer cells with acquired cell death resistance. To achieve these cancerous hallmark features, early premalignant lesions likely undergo many cycles of fractional killing of premalignant cells which inevitably will select for the most resistant subclones. 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). Binding of these ligands to their cognate receptors expressed on tumour cells can trigger regulated types of cell death. In addition to direct ligand/receptor interaction-triggered regulated cell death such as extrinsic apoptosis and necroptosis, cancer cells can also undergo selective pressure from other forms of regulated cell death including intrinsic apoptosis, ferroptosis and pyroptosis.
Our group focusses on the function of different types of cell death in cancer selection-of-the-fittest. A particular focus herein is on the selection mechanisms at work in lung and pancreatic cancers. By unravelling mechanisms of selection of the fittest cellular clone, we anticipate to gain an understanding of what these cells are selected for and thereby identify new treatment opportunities for these cancers.