Jiwon Kim

Coordinated cell rotation along a curved matrix interface can sculpt epithelial tissues into spherical morphologies. Subsequently, radially oriented invasion of multicellular strands or branches can occur by local remodelling of the confining matrix. These symmetry-breaking transitions emerge from the dynamic reciprocity between cells and matrix but remain poorly understood. Here we show that epithelial cell spheroids collectively transition from circumferential orbiting to radial invasion via bidirectional interactions with the surrounding matrix curvature. Initially, spheroids exhibit an ellipsoidal shape but become rounded as orbiting occurs. In turn, orbiting along sharper curvature results in locally stronger contractile tractions, which gradually align collagen fibres in the radial direction. Thus, the initially elongated morphology primes the matrix towards subsequent invasion of two to four strands that are roughly aligned with its major axis. We then show that orbiting can be arrested and invasion can be reversed using osmotic pressure. We also investigate coordinated orbiting in mosaic spheroids, showing that a small fraction of cells with weakened cell–cell adhesions can impede collective orbiting but still invade into the matrix. This work elucidates how symmetry breaking in tissue morphogenesis is governed by the interplay of collective migration and the local curvature of the cell–matrix interface, with relevance for embryonic development and tumour progression.

Animal cells direct their migration in response to diverse microenvironmental cues during developmental, physiological, and pathological processes. Emerging biomaterial and microfluidic technologies enable exquisite control over these external signals to manipulate cell migration, facilitating new fundamental insights and biomedical applications. Here, we highlight recent advances in cell migration assays, with particular emphasis on collective and individual epithelial invasion. First, we consider cell migration in confined geometries, either through micropatterned topographies or microchannels. Next, we address cell invasion in 3D matrix, including both natural and synthetic hydrogels. We then discuss microfluidic devices for applying flow and gradients. Finally, we consider emerging technologies and the potential for bench to bedside translation in cancer biology.

A one megapixel CMOS capacitance sensor with 10 micron pixels tracks adherent migrating cells and tissues across one square centimeter.

Animal cells can sense and "remember" the stiffness of their extracellular environment, resulting in sustained changes in form and function. Such "mechanical memory" has been previously explored using individual cells and attributed to epigenetic changes and transcriptional activity. However, it is unclear whether such memory is retained across collective cells. Here, we report that collective cells sustain mechanical memory through self-organized actin-CK18 networks spanning multiple cell lengths, even under dramatically changing mechanical environments, such as those encountered during cancer metastasis. As a case study, we modeled ovarian cancer metastasis and found that cells initially cultured on different stiffness retained distinct migratory phenotypes throughout the environmental transitions of the metastasis model. Notably, soft-primed cells, in particular, demonstrated stronger cell-cell adhesions than stiff-primed cells. Upon aggregation into multicellular spheroids, mimicking malignant spheroids found in patient ascites, the soft-primed spheroids exclusively developed a dense cage-like supracellular actin-CK18 structure at their peripheral surfaces. Furthermore, these soft-primed spheroids exhibited impeded collective invasion, instead becoming confined by the long-lasting cytoskeletal cage. Inhibition of gap junctions attenuated the formation of cytoskeletal cages, indicating that dynamic intercellular communication via gap junctions is essential for maintaining collective mechanical memory. This work demonstrates a collective mechanism of mechanical memory that is not solely dependent on epigenetic and transcriptional activation, advancing our understanding of the elevated metastatic potential of tumor cell clusters originating in stiffened matrices.

Coordinated cell rotation along a curved matrix interface can sculpt epithelial tissues into spherical morphologies. Subsequently, radially-oriented invasion of multicellular strands or branches can occur by local remodeling of the confining matrix. These symmetry-breaking transitions emerge from the dynamic reciprocity between cells and matrix, but remain poorly understood. Here, we show that epithelial cell spheroids collectively transition from circumferential orbiting to radial invasion via bi-directional interactions with the surrounding matrix curvature. Initially, spheroids exhibit an ellipsoidal shape but become rounded as orbiting occurs. However, cells gradually reorient from coordinated rotation towards outward strand invasion due to the accumulation of contractile tractions at discrete sites. Remarkably, the initial ellipsoid morphology predicts subsequent invasion of 2-4 strands roughly aligned with the major axis. We then perturb collective migration using osmotic pressure, showing that orbiting can be arrested and invasion can be reversed. We also investigate coordinated orbiting in “mosaic” spheroids, showing a small fraction of “leader” cells with weakened cell-cell adhesions can impede collective orbiting but still invade into the matrix. Finally, we establish a minimal self-propelled particle model to elucidate how collective orbiting is mediated by the crosstalk of cell-cell and cell-matrix adhesion along a curved boundary. Altogether, this work elucidates how tissue morphogenesis is governed by the interplay of collective behaviors and the local curvature of the cell-matrix, with relevance for embryonic development and tumor progression.