Pancreatic ductal adenocarcinoma (PDAC) is one of the five most lethal malignancies worldwide and survival has not improved substantially in the past 30 years. Desmoplasia (abundant fibrotic stroma) is a typical feature of PDAC in humans, and stromal activation commonly starts around precancerous lesions. It is becoming clear that this stromal tissue is not a bystander in disease progression. Cancer-stroma interactions effect tumorigenesis, angiogenesis, therapy resistance and possibly the metastatic spread of tumour cells. Therefore, targeting the tumour stroma, in combination with chemotherapy, is a promising new option for the treatment of PDAC. In this Review, we focus on four issues. First, how can stromal activity be used to detect early steps of pancreatic carcinogenesis? Second, what is the effect of perpetual pancreatic stellate cell activity on angiogenesis and tissue perfusion? Third, what are the (experimental) antifibrotic therapy options in PDAC? Fourth, what lessons can be learned from Langton's Ant (a simple mathematical model) regarding the unpredictability of genetically engineered mouse models?

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and shows resistance to any therapeutic strategy used. Here we tested small-molecule inhibitors targeting chromatin regulators as possible therapeutic agents in PDAC. We show that JQ1, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, suppresses PDAC development in mice by inhibiting both MYC activity and inflammatory signals. The histone deacetylase (HDAC) inhibitor SAHA synergizes with JQ1 to augment cell death and more potently suppress advanced PDAC. Finally, using a CRISPR-Cas9–based method for gene editing directly in the mouse adult pancreas, we show that de-repression of p57 (also known as KIP2 or CDKN1C) upon combined BET and HDAC inhibition is required for the induction of combination therapy–induced cell death in PDAC. SAHA is approved for human use, and molecules similar to JQ1 are being tested in clinical trials. Thus, these studies identify a promising epigenetic-based therapeutic strategy that may be rapidly implemented in fatal human tumors.