Department of Physics, Oregon State University, Corvallis, OR 97331.
Department of Physics, University of California San Diego, La Jolla, CA 92093.
Proc Natl Acad Sci U S A. 2021 Mar 9;118(10). doi: 10.1073/pnas.2024780118.
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.
接触引导是一种主要的物理线索，可调节癌细胞的形态和运动，并且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，纤维的无序组装会对细胞呈现出复杂的定向偏差。目前尚不清楚癌细胞如何应对这些非相干的接触引导线索。在这里，我们结合定量实验、理论分析和计算模型，研究了乳腺癌细胞对具有不同纤维排列程度的 3D 胶原 ECM 的形态和迁移反应。我们使用 ECM 纤维的方向连贯性来量化接触引导的强度，并发现更强的接触引导会使细胞更强烈地沿着纤维的主方向极化。有趣的是，对接触引导的敏感性与细胞的纵横比呈正相关，即细长的细胞比圆形细胞对 ECM 排列的反应更强烈。实验和模拟均表明，细胞-ECM 黏附以及肌动球蛋白收缩性通过在圆形和细长细胞之间诱导群体转移来调节细胞对接触引导的反应。我们还发现，细胞在导航 ECM 时会迅速改变其形态，并且 ECM 纤维连贯性会调节细胞在不同形态表型之间的转变速率。总之，我们发现整合了相互冲突的机械线索的亚细胞过程决定了细胞形态，这预测了癌症细胞在 3D ECM 中的极化和迁移动力学。
