Highlights
•Spatial multi-omics maps cachexia progression in pancreatic cancer
•SEMA4A+ tumor cells associate with muscle wasting and cachexia
•AQP9+ macrophages and LOXL2+ fibroblasts reinforce SEMA4A signaling
•A tri-cellular niche predicts postoperative and new-onset cachexia in patients
Summary
Cachexia is a major cause of morbidity in pancreatic cancer, but the cellular circuitry linking tumor progression to systemic wasting remains incompletely understood. Integrating single-cell RNA sequencing, Xenium spatial transcriptomics, multiplex immunohistochemistry, bulk transcriptomics, and functional studies across human non-cachexia, pre-cachexia, and cachexia samples, together with mouse models, we define a cachexia-associated microenvironmental niche composed of SEMA4A+ tumor cells, AQP9+ macrophages, and LOXL2+ cancer-associated fibroblasts. Mechanistically, SEMA4A-associated signaling promotes bone morphogenetic protein-2 (BMP2)-dependent acquisition of an AQP9-associated macrophage phenotype, and macrophage-derived CXCL8 activates LOXL2+ fibroblasts. LOXL2+ fibroblasts reciprocally enhance tumor cell FOSL1/SEMA4A signaling through exosomal N-glycosylated LOXL2. Spatial analyses demonstrate progressive enrichment of this niche with cachexia severity and association with postoperative development of cachexia in previously non-cachectic patients. These findings provide a framework linking local tumor ecosystem dynamics to cachexia progression.
