Cancer cell interactions with the extracellular matrix and the migration therein involve the function of adhesion receptors of the integrin family, a dynamic cytoskeleton, as well as proteolytic mechanisms to overcome tissue barriers. Recent progress in investigating tumour cell migration and associated matrix remodelling was made using three-dimensional (3D) dermis equivalents such as 3D collagen lattices or dermal explant cultures, prompting new concepts in molecular tumour invasion mechanisms and related adaptation responses. Mesenchymal HT-1080 fibrosarcoma cells as a model line migrate in an integrin-dependent manner and proteolytically cleave extracellular matrix structures. After interference with integrin and protease function, however, cancer cells can switch migration programs and thereby rescue migration by alternative mechanisms. Depending on the context of invasion, treatment with protease inhibitors or integrin antagonists can cause the mesenchymal-amoeboid transition and the collective-amoeboid transition, both generating sustained dissemination of single cells. These adaptation responses show an unexpected degree of plasticity resulting in migratory 'escape' strategies after pharmacotherapeutic intervention by prompting alternative mechanisms of cancer cell dissemination in tissues.