Targeting transcriptional addiction to pro-proliferative programs in pancreatic cancer [RNAKD]

The pancreas is a special organ which is considered both endocrine and exocrine. The exocrine pancreas gives rise to pancreatic ductal adenocarcinoma (PDAC), which accounts for the majority of pancreatic cancer cases. In recent years, various new therapeutic options for cancer patients have resulted in increased survival, but these advancements do not include PDAC patients, who still present with a 5-year survival rate of only 13%. Therefore, there is an increasing need for finding new therapeutic targets to treat PDAC. Here, we identify the chromatin binding protein HMGB2 as a promising option. HMGB2 is overexpressed in multiple cancer types and correlates with their replicative potential. Using multiple models from patient tissue to organoids and mice, we assign a key role to HMGB2 in the proliferation control of PDAC. Using single-cell multiomics, we uncover how HMGB2 affects chromatin accessibility at a plethora of cell cycle-related gene loci, thereby directly controlling their expression. We further demonstrate how HMGB2 pharmacological targeting constrains cell proliferation and accordingly propose that it represents a ubiquitous and attractive anti-proliferative target in the fight against PDAC.