A Thiadiazolopyrimidinone-Based Molecule Targeting Annexin A6 Impairs Cell Motility and Epithelial-to-Mesenchymal Transition in Pancreatic Cancer Cells Lacking Annexin A1

Pancreatic carcinoma (PC) is the most lethal malignancy due to its aggressive behavior and limited therapeutic response. Among the annexin family, Annexin A1 (ANXA1) is documented to promote PC aggressiveness, and conversely, the role of Annexin A6 (ANXA6) is less explored. Here, we report that ANXA6 is significantly upregulated in ANXA1 knockout (KO) MIA PaCa-2 cells. Using <b>LAM20</b>, our previously identified ANXA6 modulator, we show that inhibition of this protein impairs cell motility, and epithelial-to-mesenchymal transition markers, without affecting 2D/3D cell proliferation. ANXA6 siRNA-mediated knockdown reproduces <b>LAM20</b> effects, suggesting a relationship with their impact on ANXA6. Interestingly, in ANXA1 KO cells, <b>LAM20</b> reduced the migration/invasion rate differently from the ANXA1 inhibitor heparan sulfate, which retains effects on the wild-type (WT) MIA PaCa-2 counterpart. These findings suggest that in cells lacking ANXA1, ANXA6 plays a compensatory role in sustaining the aggressive phenotype, albeit to a lesser extent than in WT cells. Thus, <b>LAM20</b> represents a promising therapeutic strategy to impair PC aggressiveness. Our study provides new insights into ANXA1/ANXA6 crosstalk and introduces a novel approach to disturb PC pro-invasive mechanisms. Targeting ANXA1 and ANXA6 is relevant because, where ANXA1 is downregulated/absent, ANXA6 expression can be restored in a compensatory manner, partially sustaining tumor progression.