HDAC2 facilitates pancreatic cancer metastasis

Mortality of patients with pancreatic ductal adenocarcinoma (PDAC) is strongly connected to metastasis, a multi-step process incompletely understood. Although genetic drivers were not defined, transcriptional and epigenetic rewiring processes contribute to PDAC metastasis. However, prevention of metastasis is not possible so far. The epigenetic eraser histone deacetylase 2 (HDAC2) is connected to less differentiated PDACs. By the use of genetically defined in vivo and ex vivo models, we show that HDAC2 is a cellular fitness factor, especially for undifferentiated, mesenchymal PDAC cells. In unbiased expression profiles, we detected a core set of genes, whose expression depends on HDAC2. Strikingly, HDAC2 controls several receptor tyrosine kinases connected to mesenchymal PDACs, including PDGFRa, PDGFRb, and EGFR, which signal to the pro-survival PI3K-AKT-pathway. The HDAC2-maintained program disables the tumor-suppressive arm of the TGFb-pathway, explaining impaired metastasis formation of Hdac2-deficient PDACs in vivo.