Contact guidance is a major physical cue that modulates cancer cell morphology and motility, and is directly linked to the prognosis of cancer patients. Under physiological conditions, particularly in the three-dimensional (3D) extracellular matrix (ECM), the disordered assembly of fibers presents a complex directional bias to the cells. It is unclear how cancer cells respond to these noncoherent contact guidance cues. Here we combine quantitative experiments, theoretical analysis, and computational modeling to study the morphological and migrational responses of breast cancer cells to 3D collagen ECM with varying degrees of fiber alignment. We quantify the strength of contact guidance using directional coherence of ECM fibers, and find that stronger contact guidance causes cells to polarize more strongly along the principal direction of the fibers. Interestingly, sensitivity to contact guidance is positively correlated with cell aspect ratio, with elongated cells responding more strongly to ECM alignment than rounded cells. Both experiments and simulations show that cell–ECM adhesions and actomyosin contractility modulate cell responses to contact guidance by inducing a population shift between rounded and elongated cells. We also find that cells rapidly change their morphology when navigating the ECM, and that ECM fiber coherence modulates cell transition rates between different morphological phenotypes. Taken together, we find that subcellular processes that integrate conflicting mechanical cues determine cell morphology, which predicts the polarization and migration dynamics of cancer cells in 3D ECM.

接触引导是调节癌细胞形态和运动的主要物理线索，与癌症患者的预后直接相关。在生理条件下，特别是在三维 (3D) 细胞外基质 (ECM) 中，纤维的无序组装对细胞呈现出复杂的方向偏差。目前尚不清楚癌细胞如何对这些不连贯的接触指导线索做出反应。在这里，我们结合定量实验、理论分析和计算建模来研究乳腺癌细胞对具有不同程度纤维排列的 3D 胶原 ECM 的形态学和迁移反应。我们使用 ECM 纤维的方向相干性来量化接触引导的强度，并发现更强的接触引导会导致细胞沿着纤维的主要方向更强烈地极化。有趣的是，对接触引导的敏感性与细胞纵横比呈正相关，细长细胞对 ECM 对齐的反应比圆形细胞更强烈。实验和模拟都表明，细胞-ECM 粘附和肌动球蛋白收缩性通过诱导圆形和细长细胞之间的种群转移来调节细胞对接触引导的反应。我们还发现，在导航 ECM 时，细胞会迅速改变其形态，并且 ECM 纤维的一致性调节不同形态表型之间的细胞转换率。总之，我们发现整合相互冲突的机械线索的亚细胞过程决定了细胞形态，