Summary Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal myofibroblasts but their functional contribution remains unknown. Transgenic mice with ability to delete αSMA+ myofibroblasts in pancreatic cancer were generated. Depletion starting at either non-invasive precursor (PanIN) or the PDAC stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-mesenchymal transition and cancer stem cells, with diminished animal survival. In PDAC patients, lower myofibroblasts in their tumors also correlated with reduced survival. Suppressed immune surveillance with increased CD4+Foxp3+ Tregs was observed in myofibroblasts depleted mouse tumors. While myofibroblasts depleted tumors did not respond to Gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival. This study underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC.

No abstract

Summary The mutant form of the GTPase KRAS is a key driver of pancreatic cancer but remains a challenging therapeutic target. Exosomes, extracellular vesicles generated by all cells, are naturally present in the blood. Here we demonstrate that enhanced retention of exosomes in circulation, compared to liposomes, is due to CD47 mediated protection of exosomes from phagocytosis by monocytes and macrophages. Exosomes derived from normal fibroblast-like mesenchymal cells were engineered to carry siRNA or shRNA specific to oncogenic KRASG12D (iExosomes), a common mutation in pancreatic cancer. Compared to liposomes, iExosomes target oncogenic Kras with an enhanced efficacy that is dependent on CD47, and is facilitated by macropinocytosis. iExosomes treatment suppressed cancer in multiple mouse models of pancreatic cancer and significantly increased their overall survival. Our results inform on a novel approach for direct and specific targeting of oncogenic Kras in tumors using iExosomes.