Spatial evolution of a cachexia-promoting microenvironment in pancreatic cancer.

Authors

Yumeng Hu, Gaoyuan Lv, Hao Yuan, Zhijun Zhou, Shaobo Zhang, Yuxin Ye, Qun Chen, Yang Cai, Jingxuan Yang, Yuqing Zhang, Chao Xu, Wenyi Luo, Michael S Bronze, Courtney W Houchen, Yi-Ping Li, Jingyong Xu, Yuanyuan Zhang, Mingyang Liu, Min Li

Published in

Cell. Sep 29, 2026. Epub Sep 29, 2026.

Abstract

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.

PMID:
42810340
Bibliographic data and abstract were imported from PubMed on 30 Sep 2026.

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