Through the analysis of the Focal Adhesion Kinase (FAK) protein and the matrix metalloprotease MMP-2, both implicated in multiple steps of the metastatic spectrum, in complex multicellular tumor spheroids we show that cancer cell populations over-expressing MMP-2 or cancer-associated fibroblasts can release FAK-deficient cancer cells from their constrained metastatic fitness. Here, PTK2 is linked to neoplasm.