Cachexia-induced alterations of miR-27a-3p drive cell-type specific effects in FAPs and tumor cells that coincide...

The contribution of muscle-resident stromal cells to cancer-associated muscle wasting is poorly understood. We characterized the role of fibroadipogenic progenitors (FAPs) in pancreatic cancer-associated cachexia and investigated how dysregulated microRNAs in the tumor and FAPs drive muscle wasting. In cancer-bearing mice, FAPs engage in a chronic pro-inflammatory and pro-adipogenic program coinciding with muscle wasting. Additionally, in vitro and in vivo findings suggest that FAPs from cachectic mice cause muscle wasting, indicating that they may release pro-atrophic factors. Cancer-induced downregulation of miR-27a-3p in FAPs increased adipogenesis, whereas its upregulation in cancer cells increased proliferation and migration, highlighting the challenges of targeting pleiotropic molecules therapeutically. Knocking down miR-27a in the tumor improved both the micro- and macroenvironment of the muscle in vivo. Overall, we demonstrate that miR-27a-3p contributes to tumor progression and the dysregulation of FAPs, cooperatively driving muscle wasting. Our findings underscore the importance of tissue-specific targeting of microRNAs in cancer.