STK11 in pancreatic cancer
Pancreatic cancer is a common malignant tumor of the digestive system. It is highly aggressive, rapidly progressing, easily metastatic, and extremely difficult to treat. This research aims to analyze which gene can regulate pancreatic cancer metastasis by CRISPR/Cas9 screening that can provide an essential basis for prognostic judgment of pancreatic cancer and individualized treatment. A mouse ACF CRISPR knockout library of 3,466 sgRNAs directed against 915 genes was transfected into a mouse PDAC cell line (TB 32047) to select the genes required for cell migration by Transwell screening. After accelerated migration screening, STK11 was one of the top candidate genes whose knockout promoted migration and increased liver metastasis in mice. Mechanistic analyzes revealed that STK11 inhibition influences blood vessel morphogenesis. Interestingly, the STK11 mutant is closely associated with enhanced expression of phosphodiesterases (PDEs), especially PDE4D, PDE4B, or PDE10A. PDEs could function as a transcriptional biomarker that identifies the STK11 mutation in PDAC. The inhibitory effect of PDE inhibitors on the migration ability of STK11 mutant cells further demonstrates that PDEs are essential for cell migration in STK11 loss cells. In conclusion, this research can help adopt different therapeutic strategies for different tumors to rationalize efficacy and reduce ineffective treatment, ultimately prolonging survival and improving the quality of life of patients.