Why do rigid tumors contain soft cancer cells?*

As early as 50 AD, the Roman medical encyclopaedist Celsus recognized that solid tumors are stiffer than surrounding tissue. However, cancer cell lines are softer, which facilitates invasion. This paradox raises several questions: Does softness emerge from adaptation to mechanical and chemical cues in the external microenvironment? Or are soft cells already present inside a rigid primary tumor? We investigate primary samples from patients with mammary and cervical carcinomas on multiple length scales from tissue level down to single cells. We show that primary tumors a highly heterogeneous in their mechanical properties on the tissue level as well as cells do exhibit a broad distribution of rigidities, with a higher fraction of softer and more elongated cells compared to normal tissue. Mechanical modelling based on patient data reveals that tumors remain solid containing a significant fraction of very soft cells. Moreover, it predicts that in such tissues, softer cells spontaneously self-organize into multicellular streams, which we observe experimentallz.