A tool for predicting drug-specific cell death responses in melanoma

Markus Rehm and his team published a new study in the Journal “Cell Death and Differentiation” (Cell Death Differ. 2013 Nov;20(11):1521-1531). In this study, they were successful in predicting the best treatment option for individual melanoma cell lines by using a novel systems modelling approach. The elimination of cancer cells by a process called Apoptosis is a mainstay of anti-cancer chemotherapies. Markus Rehm and his team used quantitative data of proteins that regulate this cell death mechanism together with information on their interactions and regulatory functions to predict the treatment outcome for individual cell lines to different apoptosis-inducing drugs. Using these information they were able to select the best treatment option in up to 91% of the cases. Additionally, the investigators could identify optimal co-treatment strategies to overcome resistance in melanoma cells. Their novel approach may contribute to the development of personalized cancer treatments in the future.

The systems model was co-developed and implemented by Dr Maximilian Würstle, a postdoctoral researcher in the group of Dr Rehm. A poster designed by Dr Würstle won the “best poster” price at the European Cell Death Organisation annual conference in Paris in late September. Oral presentations of the study results were given in guest seminars and conference talks in recent months (Dermatology Clinics, University of Dresden; Mount Sinai School of Medicine, New York; 3U Cancer Conference, Dublin; CSHL Cell Death meeting, Cold Spring Harbor).

Insight into intracellular protease activities during cancer cell death

Caspases are proteases crucial for the elimination of cancer cells by apoptotic cell death. Eugenia Delgado, a PhD student in the team of Dr Markus Rehm, has now published the first study in which the contribution of caspase-2 to apoptosis initiation and execution was analysed inside individual living cells by highly sensitive biophysical FRET reporter assays (Biochim Biophys Acta. 2013 Oct;1833(10):2279-92). So far, approaches towards measuring caspase-2 activity were restricted to analyses in cell homogenates and extracts, yielded inconsistent results, and were often limited in sensitivity, thereby contributing to controversies regarding the role of caspase-2 during apoptosis. Furthermore, caspases overlap in substrate specificities, and caspase-8 as well as effector caspases may cleave optimal caspase-2 recognition motifs. The study found that limited proteolysis of caspase-2 substrates during extrinsic apoptosis initiation was attributable to caspase-8 rather than caspase-2. The contribution of caspase-2 to proteolytic activities during apoptosis execution was insignificant. In contrast to several previous studies, the authors demonstrate that caspase-2 substrate is predominantly cleaved by caspase-8 and effector caspases during canonical apoptosis signalling.