KLF5 modulates epigenetic modifications driving human pancreatic ductal adenocarcinoma metastasis [Multiome]

We previously showed that distant metastases of human pancreatic ductal adenocarcinoma (PDAC) are driven by epigenetic alterations in the primary tumor rather than by additional mutations1. However, the specific epigenetic driver genes responsible have not been identified. To identify genes modulating these changes, we performed a pooled CRISPR genetic screen and single-cell multiomics analysis using patient-derived xenograft cell lines established from a primary PDAC tumor and a distant metastasis from the same patient. We identified KLF5 as the leading epigenetic modulator regulating progression in distant metastasis. Knockdown of KLF5 selectively reduced the growth of the distant metastasis and caused a large-scale increase in heterochromatin. Single-cell multiome ATAC and gene expression analysis revealed two clusters with high KLF5 expression and increased expression and chromatin accessibility of stem cell markers and genes related to migration and epithelial to mesenchymal transition. Further, we identified two epigenetic modifiers, NCAPD2 and MTHFD1, which are regulated by KLF5 and result in these increases in heterochromatin when knocked down. These data provide a sequence of epigenetic modulators, modifiers and mediators which shape the metastatic landscape of pancreatic cancer.