Pancreatic cancer is often diagnosed at an advanced stage and is characterised by a poor prognosis and rising mortality.
Galectin-3 (Gal-3), a chimaeric protein, plays a multifaceted role in driving the progression of pancreatic adenocarcinoma (PAAD).
While its interaction with tumour microenvironment cells is well-documented, the specific mechanisms by which Gal-3 mediates tumour–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, China, and Cardiff University School of Medicine, Wales, elucidates whether the inhibition of Gal-3 expression in tumour 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 upregulated in tumors but also significantly associated with 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 pathway to increase the transcription of C–C motif chemokine 2 (CCL2) and basigin (BSG) in TAFs.
Interestingly, the Gal-3–mediated signalling cascade was shown to suppress oxidative phosphorylation in tumour 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 signalling and the BSG-FAK-ERK pathway.
Inhibition of these pathways reversed drug resistance and reduced tumour sphere formation.
Genetic testing can transform surgical decisions and family risk assessment. New tools are making it easier for all clinicians to integrate testing without specialist referrals.
Listen Now | Exclusive to The Oncology Network
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 tumour growth without adverse effects.
These findings suggest that Gal-3 inhibition in vivo can effectively potentiate the anti-tumour effect of gemcitabine.
In summary, this study demonstrates that inhibiting Gal-3 in combination with gemcitabine in the tumour 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.
Source: Compuscript Ltd
