The chimeric aptamer axl-miR-214sponge inhibits breast cancer and melanoma dissemination

TL;DR

A new chimeric aptamer called axl-miR-214sponge was shown to block the spread of breast cancer and melanoma in mice without causing toxicity.

Contribution

The development and testing of a novel chimeric aptamer that targets both miR-214 and the AXL receptor to inhibit cancer metastasis.

Findings

Axl-miR-214sponge reduced migration, invasion, and transendothelial migration in axl-positive cancer cells.

Systemic administration of axl-miR-214sponge reduced cancer dissemination in mice without toxicity.

The treatment increased levels of TFAP2C and ITGA3 while decreasing ALCAM expression in cancer cells.

Abstract

MicroRNAs (miRNAs) are often deregulated in cancer. We previously showed that inhibition of the pro-metastatic miR-214 strongly impairs tumor dissemination. We recently developed a chimeric aptamer, axl-miR-214sponge, including an oligonucleotide sequence able to inhibit miR-214 (miR-214sponge) linked to GL21.T (axl), an aptamer that binds specifically to axl, an oncogenic tyrosine kinase receptor abundantly expressed on various malignant melanoma and breast cancer cells. When axl-positive but not axl-negative cancer cells were treated with axl-miR-214sponge, reduced migration, invasion, and transendothelial migration were observed. In parallel, augmented levels of two miR-214 direct targets, TFAP2C and ITGA3, were seen. Instead, expression of ALCAM, a target of the anti-metastatic miR-148b and downstream effector of miR-214, was found to be decreased. More important, when mice carrying xenotransplants derived from triple-negative breast cancer or melanoma cells were treated in loco or systemically with the axl-miR-214sponge conjugates, reduced cancer dissemination was seen, together with increased cell death in primary tumor masses. No toxicity was noted in animals. In summary, our data suggest that axl-miR-214sponge is specific, effective, and safe in blocking axl-positive cancer cell spreading. Thus, it represents a promising targeted therapy tool to fight metastasis.

Systemic administration of the chimeric aptamer axl-miR-214sponge, formed by an oligonucleotide sequence able to inhibit miR-214 (miR-214sponge) linked to an aptamer (GL21.T) able to specifically bind the oncogenic receptor axl, was proven to reduce cancer cell dissemination in mice carrying breast cancer or melanoma cell-derived xenotransplants without toxicity signs.

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