Merlin’s disappearing act: NF2 loss conjures pancreatic cancer survival in the hostile tumor microenvironment
Sofia Ferreira, Laura D. Attardi
Sofia Ferreira, Laura D. Attardi
View: Text | PDF
Commentary

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

Abstract

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.

Authors

Sofia Ferreira, Laura D. Attardi

×

Figure 1

The role of NF2 inactivation in PDAC.

Options: View larger image (or click on image) Download as PowerPoint
The role of NF2 inactivation in PDAC. Using healthy human pancreatic aci...
Using healthy human pancreatic acinar cells, Xu et al. (9) developed an organoid-based PDAC model by overexpressing KRASG12V and inactivating the tumor suppressors TP53 and CDKN2A/P16 (termed the KPT model). A pooled CRISPR-KO screen identified NF2 as a top tumor suppressor candidate. Inactivation of NF2 in the KPT model (termed KPTN) led to multiple phenotypes associated with increased tumor aggressiveness and a poor prognosis, including enhanced invasiveness, WNT signaling independence, increased macropinocytosis via PAK1, and therapy resistance to a pan-RAS inhibitor (RASi) and gemcitabine.