靶向细胞内Galectin-3破坏BRAF V600E突变的休眠细胞播散并恢复甲状腺癌的化疗敏感性

Introduction: Papillary Thyroid Carcinoma (PTC) often exhibiting local invasion and the capacity for distant metastasis. While Galectin-3 (Gal-3) is a well-established diagnostic marker, absent in normal thyroid tissue and benign lesions, its intracellular functional role in thyroid cancer remains largely unknown. This study aimed to determine whether cell-autonomous Gal-3 in BRAF V600E mutated cells contributes directly to tumor aggressiveness by activating an invasive and metastatic program. Experimental procedures: We profiled Gal-3 expression in well-differentiated, poorly differentiated, and metastatic TC samples and used genetic modulation in TC cells to test its impact on proliferation, migration, invasion, and cell cycle. Transcriptomic and proteic profile characterization investigated the dormancy pathway and the interaction of Gal-3 with CD44v6 signaling axis to uncover intra and extra-cellular cooperative mechanisms in thyroid carcinoma progression. Synergistic anti-cancer effects of Gal-3 knockdown in combination with chemotherapy were tested both in vitro and in vivo trough ortothopic mouse models, to understand the intracellular Gal-3's impact on primary tumor growth, metastasis and chemosensitivity. New data: Our data establishes Gal-3 as a pivotal molecular character in PTC pathogenesis. Elevated Gal-3 expression is a hallmark of high-grade disease, showing a striking correlation with poorly differentiated and metastatic tumors compared to their well-differentiated counterparts, underscoring its prognostic significance. Mechanistically, the CD44v6 signaling cascade acts upstream, promoting the intracellular accumulation of Gal-3. This accumulation triggers a transcriptional program that simultaneously dictates cell cycle arrest, fuels enhanced migration and invasion, and crucially, activates a disseminated-dormant phenotype.Remarkably, disrupting Gal-3 via knockdown fundamentally destabilizes this dormant state, forcing dormant TC cells to exit quiescence and undergo outgrowth. This vulnerability translates directly into a therapeutic opportunity: combining Gal-3 silencing with standard chemotherapy profoundly sensitizes these slow-cycling, metastatic cells, achieving a synergistic enhancement of therapeutic efficacy. Conclusions: These findings unequivocally position Gal-3 as a functional driver of both invasive potential and the elusive dormant phenotype in TC. Furthermore, its modulation represents a highly promising strategy to re-sensitize slow-cycling, treatment-refractory metastatic TC cells, offering a novel avenue for treating patients with advanced disease.