Tumor cell-conditioned media drives collagen remodeling via fibroblast and pericyte activation in an in vitro premetastatic niche model

Primary tumors secrete large quantities of cytokines and exosomes into the bloodstream, which are uptaken at downstream sites and induce a pro-fibrotic, pro-inflammatory premetastatic niche. Niche development is associated with later increased metastatic burden, but the cellular and matrix changes in the niche that facilitate metastasis are yet unknown. Furthermore, there is no current standard model to study this phenomenon. Here, biofabricated collagen and hyaluronic acid hydrogel models were employed to identify matrix changes elicited by pericytes and fibroblasts after exposure to colorectal cancer-secreted factors. Focusing on myofibroblast activation and collagen remodeling, we report fibroblast activation and pericyte stunting in response to tumor signaling. In addition, we characterize contributions of both cell types to matrix dysregulation via collagen degradation, deposition, and architectural remodeling. With these findings, we discuss potential impacts on tissue stiffening and vascular leakiness and suggest pathways of interest for future mechanistic studies of metastatic cell-premetastatic niche interactions.