Multicellular force coordination constructs microchannel networks for barrier-free metastasis across extracellular matrix

Abstract

The extracellular matrix (ECM) acts as a primary physical barrier to cancer metastasis. While individual cancer cells can remodel ECM to create microchannel-like paths of least resistance, this cell-centric view overlooks the coordinated dynamics of multicellular communication. Here, we reveal that cancer cells collaboratively reprogram ECM to construct interconnected microchannel networks functioning as "superhighways" for barrier-free metastasis. Combining live-cell imaging, atomic force microscopy, and optical tweezers, we decode that the indispensable step in microchannel network construction is organized cross-convergence of adjacent channels. The convergence is precisely directed by mechanical bridges composed of aligned collagen bundles between adjacent channels, which transmit orientation cues to induce multicellular force coordination. Integrating single-cell sequencing and off-lattice agent-based model, we identify mechanically responsive leader cells enriched for integrin-RhoA/YAP signaling and matrix metalloproteinase 14, which sense bridge cues and initiate cross-convergence. Collectively, our findings unveil a self-organized metastatic network and its mechanobiological mechanisms, offering a previously unidentified framework and potential therapeutic insights for cancer metastasis.