image: (A) Analysis of the single-cell RNA-sequencing data reveals major cell types in the tumor microenvironment: epithelial cells, myeloid cells, fibroblasts, and T cells. Relationships among each cell cluster, including LGALS3-positive and LGALS3-negative subpopulations. (B) Intercellular communication between LGALS3-positive epithelial cells (LGALS3+ Epi)/LGALS3-negative epithelial cells (LGALS3− Epi) and neighboring cells. The red arrows indicate significant differences between the Epi and TAF groups. (C) Cell–cell crosstalk, which involves ligand–receptor signaling and cytokine secretion/uptake, indicates that the PPIA-BSG pathway is strongly associated with LGALS3+ Epi in combination with TAFs. (D) Relationships between PPIA and LGALS3 in PAAD from the TCGA database. (E) PPIA expression is greater in most solid tumor types than in normal tissues. The red bars represent tumors, and the black bars represent normal tissues. (F) Individuals with low PPIA expression have prolonged overall survival in PAAD. Cutoff: 50%. (G) The radar chart displays the chromatin immunoprecipitation results for inflammatory factors. The blue arrows show the fold changes in the cytokines that are highly expressed in HPSCs/Gal-3 cells compared with the control. (H) Real-time quantitative PCR was used to validate the up-regulation of CCL2 expression at the mRNA level via rGal-3 treatment. (I) ELISA further validated the increase in CCL2 expression at the protein level in Gal-3-producing HPSCs. (J) Analysis of the single-cell RNA-sequencing data revealed a strong focus on the PPIA-BSG pathway in CCL2-positive fibroblasts. Red indicates a large difference between LGALS3+ Epi and LGALS3− Epi. (K) Protein–protein interaction network analysis via the STRING database revealed significant interactions between LGALS3, BSG, PPIA, CCL2, CCR2, PPP3CA, and NFATC2. “∗" indicates statistical significance. Gal-3, galectin-3; TAF, tumor-associated fibroblast; LGALS3, lectin galactoside-binding soluble 3; PPIA, peptidylprolyl isomerase A; BSG, basigin; PAAD, pancreatic adenocarcinoma; HPSCs, human pancreatic stellate cells; CCL2, C–C motif chemokine 2; CCR2, C–C motif chemokine receptor 2; PPP3CA, protein phosphatase 3 catalytic subunit alpha; NFATC2, nuclear factor of activated T cells 2.
Credit: Yaheng Wu, Guo An, Jia Tong, Wenlong Zhang, Zhihua Tian, Bin Dong, Xijuan Liu, Lin Zhao, Chunxian Ye, Jingtao Liu, Wei Zhao, Huachong Ma
Pancreatic cancer is often diagnosed at an advanced stage and is characterized by a poor prognosis and rising mortality. Galectin-3 (Gal-3), a chimeric protein, plays a multifaceted role in driving the progression of pancreatic adenocarcinoma (PAAD). While its interaction with tumor microenvironment cells is well-documented, the specific mechanisms by which Gal-3 mediates tumor–stromal interactions and promotes metabolic reprogramming linked to drug resistance remain unclear.
This research, published in the Genes & Diseases journal by a team from Capital Medical University, Peking University Cancer Hospital & Institute, Shandong First Medical University, and Cardiff University School of Medicine elucidates whether the inhibition of Gal-3 expression in tumor or stromal cells can improve the efficacy of gemcitabine, a standard chemotherapeutic agent for PAAD.
Analysis of multiple RNA sequencing public datasets revealed that Gal-3 is not only remarkably up-regulated in tumors but also significantly associated with the tumor-associated fibroblasts (TAFs) in PAAD patients. Notably, high Gal-3 expression correlated strongly with poor patient outcomes in pancreatic cancer. Using a co-culture model of PAAD cells and pancreatic stellate cells, the researchers demonstrated that Gal-3 mediated the Ca2+/−calcineurin–NFAT pathway to increase the transcription of C–C motif chemokine 2 (CCL2) and basigin (BSG) in TAFs.
Interestingly, the Gal-3–mediated signaling cascade was shown to suppress oxidative phosphorylation in tumor cells. Elevated CCL2, secreted by Gal-3-activated TAFs, inhibited NADPH oxidase 1 (NOX1) activity, reducing ROS levels, mitochondrial ATP production, and oxygen consumption. Additionally, Gal-3 induced the expression of CCL2 and BSG via calcium-dependent calcineurin (CALN) dephosphorylation of nuclear factor of activated T-cells 1 (NFAT1), promoting their transcription in TAFs.
Further investigations revealed that Gal-3 enhances gemcitabine resistance via two mechanisms, CCL2-CCR2 signaling and the BSG-FAK-ERK pathway. Inhibition of these pathways reversed drug resistance and reduced tumor sphere formation. In orthotopic pancreatic xenograft models, co-treatment with modified citrus pectin (MCP)—a natural Gal-3 inhibitor—and AC-73, in combination with gemcitabine, significantly reduced tumor growth without adverse effects. These findings suggest that Gal-3 inhibition in vivo can effectively potentiate the anti-tumor effect of gemcitabine.
In summary, this study demonstrates that by inhibiting Gal-3 in combination with gemcitabine in the tumor microenvironment represents a valuable innovation in the pharmacological treatment of pancreatic cancer. Overall, given its food-derived origin and safety profile, MCP presents a promising avenue for further development as an adjunctive therapy in pancreatic cancer.
Reference
Title of Original Paper: Galectin-3 in tumor-stromal cells enhances gemcitabine resistance in pancreatic adenocarcinoma by suppressing oxidative phosphorylation
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101702
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