Barbara Grünwald

Abstract Pancreatic ductal adenocarcinoma remains one of the deadliest malignancies, characterized by late diagnosis, aggressive biology and limited therapeutic success. Advances in multiagent chemotherapy have improved outcomes across disease stages, whereas precision medicine approaches are reshaping treatment paradigms. Personalized RNA vaccines and oncogenic KRAS-directed agents represent emerging immunological and molecular frontiers.

Multidimensional molecular profiling advances have begun to match the complexity of cancer, and tumours are now seen as complex ecosystems. We postulate that a shift in comprehension is needed to synthesize actionable insights — tumour tissues are heterogeneous but not disordered and propagate their functions by a considerable level of self-organization.

Highlights • Mammary epithelial cells exhibit differential DDR protein expression based on cell lineage • Independent of the cell cycle, the basal lineage exhibits lower HR repair capacity • Basal progenitors are intrinsically sensitive to PARP inhibitors • Breast tumors with a basal proteomic profile also show PARP inhibitor sensitivity Summary It is widely assumed that all normal somatic cells can equally perform homologous recombination (HR) and non-homologous end joining in the DNA damage...