Merlin's disappearing act: NF2 loss conjures pancreatic cancer survival in the hostile tumor microenvironment.

Pancreatic cancer cells "live on the edge," starved of nutrients, compressed by abundant stiff stroma, and deprived of oxygen. In this issue, Xu et al. leveraged human pancreas organoid-based CRISPR screens to identify new driver genes in pancreatic ductal adenocarcinoma (PDAC) development. Neurofibromatosis type 2 (NF2) emerged as the top tumor suppressor, whose loss enhances PDAC malignancy. Inactivation of NF2, which encodes the protein Merlin, promoted growth factor independence and enhanced macropinocytosis upon nutrient deprivation. Thus, NF2 status dictates the adaptability of pancreatic tumors under nutrient limitation, with NF2 inactivation endowing PDACs with the ability to survive the constraints of the harsh tumor microenvironment.