ODF2 maintains centrosome cohesion by restricting ß-catenin accumulation.

The centrosome, as the main microtubule-organizing center, safeguards chromosome segregation by supporting the bipolar spindle. Centrosome aberrations are causally related to chromosome segregation disorders, both characterizing cancer cells. Thus, a restriction to only having one centrosome per cell and cell cycle-dependent duplication of the centrosome is mandatory. Duplicated centrosomes remain physically connected, in order to function as a single entity, until onset of mitosis when centrosome disjunction is licensed by disassembly of linker proteins and accumulation of ß-catenin. The crucial role ß-catenin plays in centrosome disjunction inevitably demands for restricting its premature accumulation. ODF2 (also known as cenexin) is an essential centrosomal component, but its relevance for the interphase centrosome has not been elucidated. We show here that ODF2 plays a central role in centrosome cohesion. Depletion of ODF2 induces premature centrosome splitting and formation of tripolar spindles that are likely caused by the observed accumulation of centrosomal ß-catenin. Our data collectively indicate that ODF2 restricts ß-catenin accumulation at the centrosome, thus preventing premature centrosome disjunction.

A Novel AMPK Inhibitor Sensitizes Pancreatic Cancer Cells to Ferroptosis Induction.

Cancer cells must develop strategies to adapt to the dynamically changing stresses caused by intrinsic or extrinsic processes, or therapeutic agents. Metabolic adaptability is crucial to mitigate such challenges. Considering metabolism as a central node of adaptability, it is focused on an energy sensor, the AMP-activated protein kinase (AMPK). In a subtype of pancreatic ductal adenocarcinoma (PDAC) elevated AMPK expression and phosphorylation is identified. Using drug repurposing that combined screening experiments and chemoproteomic affinity profiling, it is identified and characterized PF-3758309, initially developed as an inhibitor of PAK4, as an AMPK inhibitor. PF-3758309 shows activity in pre-clinical PDAC models, including primary patient-derived organoids. Genetic loss-of-function experiments showed that AMPK limits the induction of ferroptosis, and consequently, PF-3758309 treatment restores the sensitivity toward ferroptosis inducers. The work established a chemical scaffold for the development of specific AMPK-targeting compounds and deciphered the framework for the development of AMPK inhibitor-based combination therapies tailored for PDAC.