@article{Wu2025, 
author = {Yaheng Wu and Guo An and Jia Tong and Wenlong Zhang and Zhihua Tian and Bin Dong and Xijuan Liu and Lin Zhao and Chunxiang Ye and Jingtao Liu and Wei Zhao and Huachong Ma},
title = {Galectin-3 in tumor-stromal cells enhances gemcitabine resistance in pancreatic adenocarcinoma by suppressing oxidative phosphorylation},
year = {2025},
journal = {Genes & Diseases},
volume = {12},
number = {5},
pages = {101702},
keywords = {CCL2, Galectin-3, Gemcitabine, Pancreaticstellate cells, Pancreatic adenocarcinoma},
url = {https://www.sciopen.com/article/10.1016/j.gendis.2025.101702},
doi = {10.1016/j.gendis.2025.101702},
abstract = {Galectin-3 (Gal-3) plays a multifaceted role in the development and progression of pancreatic adenocarcinoma (PAAD), which is associated with a poor prognosis. Its interaction with tumor microenvironment cells has been reported. However, the Gal-3-mediated tumor–stromal interaction and induced energy metabolism associated with drug resistance remain unknown. Our previous study has reported that Gal-3 secretion from tumor cells and inflammatory cytokine dependency are therapeutic targets. In this study, we revealed that the expression of Gal-3 was not only remarkably up-regulated in tumors but also significantly associated with the tumor-associated fibroblasts of PAAD patients. A coculture model of PAAD cells and pancreatic stellate cells revealed that Gal-3 mediated the Ca2+/−calcineurin–NFAT pathway to increase the transcription of CCL2 and BSG in tumor-associated fibroblasts. These findings ultimately lead to the observation of low energy metabolism in tumor cells. Particularly, mitochondrial oxidative phosphorylation was functionally arrested in Gal-3-high tumor cells, as demonstrated by a lower oxygen consumption rate and mitochondrial ATP production through abnormal mitochondrial morphology. The inhibition of the CCL2-CCR2 and PPIA-BSG pathways indicated the restoration of gemcitabine sensitivity when drug resistance was elicited by Gal-3. Oral administration of the natural Gal-3 inhibitor modified citrus pectin extract (MCP) showed therapeutic effect for Gal-3-activated tumors and stromal cells in orthotopic pancreatic xenograft models. Hence, our findings offer insights into the fact that low mitochondrial metabolism is dependent on Gal-3 activation-mediated gemcitabine resistance through tumor–stromal interactions.}
}