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

TL;DR

A new molecule targeting Annexin A6 reduces aggressive traits in pancreatic cancer cells that lack Annexin A1, offering a potential new treatment approach.

Contribution

The study introduces LAM20, a molecule targeting Annexin A6, as a novel therapeutic strategy to reduce pancreatic cancer aggressiveness in ANXA1-deficient cells.

Findings

ANXA6 is upregulated in ANXA1 knockout pancreatic cancer cells, contributing to aggressive behavior.

LAM20 inhibits cell motility and epithelial-to-mesenchymal transition markers without affecting proliferation.

ANXA6 knockdown mimics the effects of LAM20, indicating its role in sustaining tumor aggressiveness in ANXA1-deficient cells.

Abstract

What are the main findings?
Annexin A6 is upregulated in the absence of ANXA1. ANXA6 expression increases in ANXA1 knockout human pancreatic cancer MIA PaCa-2 cells, sustaining aggressive behavior.LAM20 targeting Annexin A6 impairs cell aggressiveness. Inhibition of Annexin A6 by LAM20 reduces cell motility and markers of epithelial-to-mesenchymal transition without affecting proliferation.

Annexin A6 is upregulated in the absence of ANXA1. ANXA6 expression increases in ANXA1 knockout human pancreatic cancer MIA PaCa-2 cells, sustaining aggressive behavior.

LAM20 targeting Annexin A6 impairs cell aggressiveness. Inhibition of Annexin A6 by LAM20 reduces cell motility and markers of epithelial-to-mesenchymal transition without affecting proliferation.

What are the implications of the main findings?
Dual therapeutic potential against aggressive pancreatic cancer. Targeting ANXA6, in addition to ANXA1, may provide a complementary approach to limit pancreatic cancer invasiveness.

Dual therapeutic potential against aggressive pancreatic cancer. Targeting ANXA6, in addition to ANXA1, may provide a complementary approach to limit pancreatic cancer invasiveness.

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 LAM20, 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 LAM20 effects, suggesting a relationship with their impact on ANXA6. Interestingly, in ANXA1 KO cells, LAM20 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, LAM20 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.

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