Stroma-derived Insulin-like growth factors enhance chemoresistance in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest cancers and more effective therapies are urgently needed. Resistance to therapy is one of the biggest challenges in cancer treatment, including PDA. One dominant player in drug resistance is the presence of a rich pro-tumoral microenvironment. Tumor associated macrophages (TAMs) and myofibroblasts are key drivers of this pro-tumoral microenvironment, and have been associated with drug resistance in many cancers. However, our understanding of the molecular mechanisms by which TAMs and fibroblasts contribute to chemoresistance is still emerging. In these studies, we found that TAMs and myofibroblasts directly support chemoresistance of pancreatic cancer cells by secreting Insulin-like growth factors 1 and 2 (IGFs), which activate Insulin/IGF receptors on pancreatic cancer cells. Immunohistochemical analysis of biopsies from pancreatic cancer patients revealed that 3 72% of the patients express activated Insulin/IGF receptors on the tumor cells, and this positively correlates with increased CD163+ TAMs infiltration. Importantly, in vivo, we found that TAMs and myofibroblasts are the main sources of IGF production, and pharmacological blockade of IGFs sensitized pancreatic tumors to gemcitabine. These findings suggest that inhibition of IGFs in combination with chemotherapy could benefit pancreatic cancer patients, and that Insulin/IGF1R activation may be used to identify pancreatic cancer patients who could benefit from a combination of chemotherapy with anti-IGF signaling inhibitors.