LS² Annual Meeting 2027

Cancer therapies have traditionally focused on inhibiting disease-driving proteins. An emerging alternative is to reprogram cellular circuitry by chemically rewiring protein function, interactions, localization, and fate. In this lecture, I will discuss recent advances in induced-proximity pharmacology and chemical biology that enable the rational manipulation of biological networks beyond conventional inhibition. Drawing on examples from targeted protein degradation, molecular glue discovery, transcriptional reprogramming, and chemically induced post-translational modifications, I will illustrate how small molecules can redirect endogenous cellular machinery to create new therapeutic mechanisms. These studies reveal opportunities to convert previously undruggable cancer dependencies into tractable therapeutic targets and suggest a broader framework in which medicines act not merely as inhibitors, but as programmable agents that rewire biological circuits. Together, these approaches point towards the possibility of re-imagining cancer therapy.  

Organelles such as centrosomes, nucleoli or mitochondria perform well-known common functions in all cell types. However, we found a surprisingly large degree of differences in composition in the context of development, disease and direct reprogramming. For example, the centrosome of human neural stem cells differs by more than half of its proteome from the one in neurons (O’Neill et al., Science 2022). Such cell type-specific composition also explains why some ubiquitous proteins have organ-specific defects, when mutated in patients, as they are only at a specific organelle in specific cell types. I will explain this for the splicing protein PRPF6 that plays specific roles at the centrosome in neural stem cells which is relevant for the disease periventricular heterotopia. I will then turn to organellar heterogeneity in direct neuronal reprogramming and discuss the role of mitochondria heterogeneity in this process and how to overcome hurdles in this conversion process due to late change of the mitochondrial proteome to a neuronal identity. I will then talk briefly about nucleolar heterogeneity, before turning to the cytoskeleton in the nucleus. I will talk about the discovery of a large number of microtubule-associated proteins in the nucleus, and discuss how the nuclear role of one of them affects neural stem cell fate and causes disease when mutated in patients. Taken together, these data highlight the concept of multiplying protein function with different roles at different organelles or cell compartments with relevance in development, disease and repair.