The mechanics and dynamics of cancer cells sensing noisy 3D contact guidance

Menée in vitro et à l'aide d'une modélisation, cette étude analyse l'effet de l'organisation spatiale des fibres de la matrice extracellulaire sur la polarisation et la migration des cellules mammaires cancéreuses

Résumé en anglais

The spatial organization of ECM fibers biases the polarization and migration of cancer cells, a phenomenon known as contact guidance which is directly linked to the clinical outcome of cancers. In physiological conditions, ECM fibers do not align perfectly in parallel. Therefore, we study the morphological and migrational response of breast cancer cells to ECM fibers aligned to various degrees. We identify the cell’s aspect ratio as an integrated biomarker that determines its sensitivity to contact guidance cues. We also find that the level of ECM alignment modulates transitions between cells of differing morphology. Taken together, we show that cells integrate complex mechanical cues to determine their morphodynamics, thereby controlling polarization and migration in 3D ECM.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.The images in the figures as well as additional microscopy images of the experiments are available at https://figshare.com/account/home#/projects/96863. The cellular Potts model simulation codes are available at https://github.com/caoys/cell-contact-cues.git.