Aging and freezing of active nematic dynamics of cancer-associated fibroblasts by fibronectin matrix remodeling

In the initial cancer stages, cancer-associated fibroblasts (CAFs) create a capsule around tumors. Exhibiting an elongated morphology, CAFs align with each other, closely resembling nematic ordering in liquid crystal physics. While these aligned CAFs may act as a defensive barrier hindering tumor expansion, inherent topological defects could represent weak spots, facilitating cancer cell dissemination. CAFs play a pivotal role in the genesis and remodeling of the extracellular matrix (ECM), with ECM proteins, especially fibronectin, reciprocally modulating CAF alignment and coherence. Yet, the intricate feedback loops between fibronectin deposition and CAF structuring remain largely unexplored. Here, we combined CAF live imaging, traction force microscopy, ECM microfabrication, and theoretical modeling to assess how the ECM influences the dynamics of nematically ordered CAFs. We found that CAFs dynamically orchestrate a fibronectin network that mirrors their nematic ordering. Over time, this passive nematic ordering of fibronectin, in turn, steers CAF rearrangement. Contrary to most cellular systems where defects remain dynamic at a steady state, our data highlights that the ECM/CAF interplay profoundly alters the behavior of both CAF and ECM nematics, leading to aging - massive slow down and even freezing of defect dynamics. This leads to a scenario where aligned areas and defects in CAFs layer are spatially and temporally fixed, yet active - exerting forces at the substate and transmitting forces between cells. Such a state could introduce localized vulnerabilities in the CAF layer, potentially promoting cancer cell spreading. ### Competing Interest Statement The authors have declared no competing interest.