A conserved transcriptional signature supports metastatic colonisation of the liver by pancreatic cancer cells

Whether pancreatic cancer cells successfully metastasise to the liver depends on complex interactions between cancer cells and the liver microenvironment, the details of which remain largely unknown. In this study, we provide evidence for a transcriptional signature, involving active MYC and repressed interferon response, that supports pancreatic cancer cells in colonising the liver. The “MYC-high/Interferon-low” signature was uncovered by comparing transcriptional profiles of human pancreatic cancer cell lines with their liver metastatic potential in mice. We confirmed the physiological relevance of this signature in two independent patient sample datasets. First, in a 187-sample study of bulk RNA sequencing of primary tumor and metastatic tissue from PDAC patients, we found an enrichment in the MYC-high/Interferon-low signature in liver metastases over primary tumor, that was not present in other metastatic sites. Second, we used a single cell-RNA sequencing dataset combined with validation experiments to show that PDAC cells are the origin of this signature in vivo and that MYC and interferon activity are negatively correlated at the cellular level. This analysis reveals a potential route to therapeutic targeting of the precursor cell populations of deadly liver metastases in pancreatic cancer.