Softness or Stiffness What Contributes to Cancer and Cancer Metastasis?

Beyond the genomic and proteomic analysis of bulk and single cancer cells, a new focus of cancer research is emerging that is based on the mechanical analysis of cancer cells. Therefore, several biophysical techniques have been developed and adapted. The characterization of cancer cells, like human cancer cell lines, started with their mechanical characterization at mostly a single timepoint. A universal hypothesis has been proposed that cancer cells need to be softer to migrate and invade tissues and subsequently metastasize in targeted organs. Thus, the softness of cancer cells has been suggested to serve as a universal physical marker for the malignancy of cancer types. However, it has turned out that there exists the opposite phenomenon, namely that stiffer cancer cells are more migratory and invasive and therefore lead to more metastases. These contradictory results question the universality of the role of softness of cancer cells in the malignant progression of cancers. Another problem is that the various biophysical techniques used can affect the mechanical properties of cancer cells, making it even more difficult to compare the results of different studies. Apart from the instrumentation, the culture and measurement conditions of the cancer cells can influence the mechanical measurements. The review highlights the main advances of the mechanical characterization of cancer cells, discusses the strength and weaknesses of the approaches, and questions whether the passive mechanical characterization of cancer cells is still state-of-the art. Besides the cell models, conditions and biophysical setups, the role of the microenvironment on the mechanical characteristics of cancer cells is presented and debated. Finally, combinatorial approaches to determine the malignant potential of tumors, such as the involvement of the ECM, the cells in a homogeneous or heterogeneous association, or biological multi-omics analyses, together with the dynamic-mechanical analysis of cancer cells, are highlighted as new frontiers of research.