In vivo multiscale measurements of solid stresses in tumors reveal scale-dependent stress transmission

Abstract Solid stress, one of the physical hallmarks of cancer, affects trafficking and infiltration of immune cells, promotes metastasis and tumorigenic pathways, and impedes therapeutic delivery. Despite these clinical ramifications, questions remain regarding the origins and consequences of solid stresses and the differential response of tumor versus normal cells to solid stresses. Answering these fundamental questions requires probing solid stresses at the cellular scale, where biological and immunological responses manifest, as well as in vivo, where the complexities of the tumor microenvironment are present. Here, we report the first in vivo and multi-scale measurements of solid stress in mouse models of breast cancer using multi-modal intravital microscopy of deformable hydrogels complemented with mathematical modeling. Utilizing the capabilities of these methods, such as the high-resolution, longitudinal, and 3-D measurements of local solid stress, we measure and compare solid stresses (i) at the single cell vs tissue scale, (ii) primary vs metastatic tumors, (iii) in vivo vs in vitro settings, and (iv) in vivo vs post-mortem. Surprisingly, we find solid stress transmission is scale-dependent, as tumor cells experience a factor of 6 reduction in stress in comparison to stress measured at the tissue scale. This finding implicates the presence of potential biophysical mechanisms that tumor cells utilize to protect themselves against lethally high solid stresses. This insight into the scale-dependence of solid stress genesis will further inform the discovery of new therapeutic strategies that sensitize cancer cells to solid stresses to induce cell death.