A KLF5's domino effect drives metastatic pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer mortality in the U.S., where more than 80% of the cases are diagnosed with metastatic PDAC (mPDAC). In this study, Maeda et al. utilized a CRISPR screen in human patient-derived xenografts from primary and lung metastatic tumors and identified the transcription factor KLF5 as an upstream modulator regulating the mPDAC phenotype. Using a combination of biochemical and molecular experiments together with single-cell genome-wide assays, the authors discovered that KLF5 induces epigenetic modifiers including NCAPD2 and MTHFD1, which in turn regulate the expression of a distinct gene profiles controlling the biology of mPDAC. Altogether, the authors defined a cascade of events acting as a domino effect triggered by KLF5, modifying the epigenetic landscape in mPDAC to support metastatic growth.