Tumors grow within confining tissue microenvironments, which are often stiffer than healthy tissue and are viscoelastic, exhibiting a time-dependent response to mechanical loading or deformation. Here, we investigated how confinement and matrix mechanics, including stiffness and viscoelasticity, mediate breast tumor spheroid growth and morphology. Single-cell and multicellular spheroids of MCF7 breast cancer cells were encapsulated in ligand-free alginate hydrogels of varying stiffnesses (1–5 kPa) and degrees of viscoelasticity (stress relaxation halftimes of 30–18,000 s) which spanned the range relevant to healthy and early invasive breast cancer. Strikingly, enhanced viscoelasticity promoted symmetry breaking across various stiffnesses, as spheroids in viscoelastic matrices developed large multicellular bulges into the matrix and evolved into ellipsoidal morphologies. While asymmetric proliferation was not responsible for symmetry breaking, symmetry breaking and final ellipsoidal morphologies depend on confinement, with ellipsoids rapidly recovering spherical morphologies when the surrounding matrix was dissociated. Interestingly, symmetry breaking in a spheroid occurs at a distinct time point, which can be explained by local plastic yielding of the surrounding matrix. We propose that as the tumor expands, solid stress accumulates until some region of matrix surrounding the spheroid undergoes plastic yielding. Subsequently, when this pressurization shell breaks, cells in the interior of the spheroid rapidly flow outward from the high-pressure core into the lower pressure periphery. These findings highlight a potential mechanical pathway for tumor invasion whereby solid stress accumulation drives rapid symmetry breaking and burst-like cellular flow to the invasive front.
Lau et al. (Sun,) studied this question.