Adipose-mimetic granular hydrogels uncover biophysical cues driving breast cancer invasion

Breast cancer cells invade collagen type I-rich mammary adipose tissue during initial stages of metastasis, but how adipocyte mechanics regulate this process remains unclear. To elucidate these connections, we quantified the size and stiffness of primary adipocytes and replicated these properties using tunable polyacrylamide (PAAm) beads. Subsequently, we embedded these beads into type I collagen to form 3D granular hydrogels mimicking native adipose tissue architecture. Bead-embedded hydrogels demonstrated increased breast cancer cell invasion and collagen fiber organization relative to beadless controls, and cells invaded more readily in systems with decreased bead stiffness. Similarly, Discrete Element Method simulations revealed that soft beads promoted invasion by deforming in response to confined cancer cell migration. These trends were validated in vivo via intravital imaging of murine mammary tumors. Collectively, our data suggest that adipocyte mechanics regulate breast cancer invasion by coordinating both matrix architecture and cellular confinement.