Broad targeting of the cell adhesion machinery: Cancer cell detachment triggered by the alpha1-oleate complex.

Abstract

A new approach to targeting cell adhesion in oncology was recently suggested by observations made in patients with bladder cancer. Intravesical alpha1-oleate treatment triggered rapid tumor cell detachment into the urine and a parallel reduction in tumor number and size. This study identified alpha1-oleate as a potent inhibitor of multiple cell adhesion families in shed cells and tumor biopsies from treated patients, confirmed in cellular models. Alpha1-oleate targeted claudins and focal adhesion constituents and disrupted tight junctions, focal adhesions, and adherens junctions, but gap junctions or desmosomes were not affected. The effects on cell adhesion were dose dependent, with stronger cell detachment and broader inhibition of adhesion-associated genes in patients treated with 8.5 mM of alpha1-oleate than the 1.7 mM dose. These acute and sustained effects identify cell detachment as a contributor to the anti-tumor effects observed clinically. AlphaFold predictions identified claudins and the focal adhesion targeting (FAT) domain of focal adhesion kinase (FAK) as potential alpha1-oleate targets, but inhibitors of claudin and FAK phosphorylation showed less potent effects than alpha1-oleate on cell detachment. The broad effect of alpha1-oleate on the cell adhesion machinery is unprecedented and suggests that therapeutic targeting of the cell adhesion machinery by alpha1-oleate should be further explored.