Rigid tumors contain soft cancer cells

Abstract

Palpation, as already mentioned in the ancient Egyptian medical text Ebers Papyrus, utilizes that solid tumors are stiffer than the surrounding tissue. However, cancer cell lines tend to soften, which may intuitively foster invasion by enhancing the ability of cancer cells to squeeze through dense tissue. This paradox raises questions besides the oxymoron itself: Does softness emerge from adaptation to the external microenvironment? Or are soft cells already present inside a rigid primary tumor mass to support cancer cell unjamming? We investigate primary tumor explants from patients with breast and cervix carcinomas on multiple length scales from the tissue level down to single cells. We find that primary tumors are highly heterogeneous in their mechanical properties. From the tissue level this heterogeneity persists down to the scale of individual cells in cancer cell clusters, resulting in a broad distribution of cell rigidities with a higher fraction of softer, more squeezable cells. Plus, squeezed cell shapes correlate with cancer cell motility. Mechanical modelling based on patient data reveals that a tumor mass as a whole is able to maintain a rigid, solid behavior even when it contains a significant fraction of very soft cells. Cell softening induced cancer cell unjamming generates heterogeneous cancer cell clusters with a solid backbone of rigid cells surrounded by soft motile cells.

Stress percolation criticality of glass to fluid transition in active cell layers

“…This is primarily based on the application of two-dimensional vertex models [19,27], a voronoi based variant endowed with motility [28] and experiments on a range of epithelial systems [20] underlining the role of geometrical constraints. More recent studies highlight the role of two types of percolations based on (i) cell connectivity [29] and (ii) edge tension network [30,31]. In particular, experiments on a zebrafish blastoderm [8], a non-confluent cell system with synchronous cell divisions, show a solid-fluid transition at the onset of zebrafish morphogenesis.…”

“…This transition is linked to a rigidity percolation based on cell connectivity [29]. On the other hand, application of a vertex model to het- erogeneous cell layers [30] and experiments on primary tumour explants [31] show rigidity percolation based on edge tension network gives rise to finite shear modulus in tumor explants consisting of heterogeneous mixture of soft and stiff cancer cells. Notwithstanding these seminal and important contributions, the universality of the transition between active solid (glass-like) and fluid phases in cellular systems and its broader applicability is yet to be established [7,29,[32][33][34][35][36][37].…”

Impact of Viscosity on Human Hepatoma Spheroids in Soft Core-Shell Microcapsules

“…For instance, solid tumors, such as breast or cervical ones are often more rigid than their surrounding healthy tissues. [7,8] However, rigid tumor cores may be surrounded by softer 'layers' of cells that are more deformable, compared to those in healthy tissue and rigid cores. This decreased stiffness potentially enhances the tumor ability to navigate through the surrounding tissues.…”

“…This decreased stiffness potentially enhances the tumor ability to navigate through the surrounding tissues. [8,9] While there is a growing interest among scientists from various disciplines in investigating the influence of mechanical stimuli on the properties of the cells (see details in Table S1), our current understanding of the scaled-up cancer cell assemblies in response to physical, and particularly mechanical properties of the environment, remains limited. Therefore, further investigations are necessary to expand our knowledge in this area.…”