Metabolic reprogramming by mutant GNAS creates an actionable dependency in intraductal papillary mucinous neoplasms of the pancreas.

BACKGROUND

Oncogenic 'hotspot' mutations of and are two major driver alterations in intraductal papillary mucinous neoplasms (IPMNs), which are precursors to pancreatic ductal adenocarcinoma. We previously reported that pancreas-specific and co-expression in p48; Kras; Rosa26; Tg (TetO-Gnas) mice (' mice) caused development of cystic lesions recapitulating IPMNs.

OBJECTIVE

We aim to unveil the consequences of mutant expression on phenotype, transcriptomic profile and genomic dependencies.

DESIGN

We performed multimodal transcriptional profiling (bulk RNA sequencing, single-cell RNA sequencing and spatial transcriptomics) in the ' autochthonous model and tumour-derived cell lines ( cells), where expression is inducible. A genome-wide CRISPR/9 screen was conducted to identify potential vulnerabilities in co-expressing cells.

RESULTS

Induction of -and resulting Galpha signalling-leads to the emergence of a gene signature of gastric (pyloric type) metaplasia in pancreatic neoplastic epithelial cells. CRISPR screening identified the synthetic essentiality of glycolysis-related genes and in ; co-expressing cells. Real-time metabolic analyses in cells and autochthonous model confirmed enhanced glycolysis on induction. Induction of made expressing cells more dependent on glycolysis for their survival. Protein kinase A-dependent phosphorylation of the glycolytic intermediate enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) was a driver of increased glycolysis on induction.

CONCLUSION

Multiple orthogonal approaches demonstrate that and co-expression results in a gene signature of gastric pyloric metaplasia and glycolytic dependency during IPMN pathogenesis. The observed metabolic reprogramming may provide a potential target for therapeutics and interception of IPMNs.