TY - JOUR T1 - Tumor invasion as non-equilibrium phase separation JF - bioRxiv DO - 10.1101/2020.04.28.066845 SP - 2020.04.28.066845 AU - Wenying Kang AU - Jacopo Ferruzzi AU - Catalina-Paula Spatarelu AU - Yu Long Han AU - Yasha Sharma AU - Stephan A. Koehler AU - James P. Butler AU - Darren Roblyer AU - Muhammad H. Zaman AU - Ming Guo AU - Zi Chen AU - Adrian F. Pegoraro AU - Jeffrey J. Fredberg Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/04/29/2020.04.28.066845.abstract N2 - The early malignant tumor invades surrounding extracellular matrix (ECM) in a manner that depends upon material properties of constituent cells and ECM. Biophysical mechanisms remain unclear, however. Using a multicellular spheroid embedded within an engineered three-dimensional matrix, we show here the potential for coexistence of solid-like, fluid-like, and gas-like phases of the cellular collective described by a jamming phase diagram. Depending upon cell type (MCF-10A vs. MDA-MB-231) and ECM density (1 to 4 mg/ml collagen), cancer cells within the spheroid display a variety of collective behaviors, including a non-migratory jammed phase and a migratory unjammed phase. At a critical collagen density, unjammed cancer cells at the spheroid periphery transition in an almost switch-like fashion between distinct modes of invasion. In the case of MDA-MB-231, for example, we find that when ECM density is 2 mg/ml or smaller single cells and cell clusters scatter from the spheroid periphery in the form of discrete gas-like particles, but when ECM density is 3 mg/ml or greater these cells flow collectively from the spheroid periphery in continuous fluid-like invasive branches. These findings suggest coexistence within the spheroid mass of multiple material phases of the cellular collective –solid-like, fluid-like, and gas-like– in a manner that is superficially similar to common inanimate multiphasic systems at thermodynamic equilibrium, but here arising in living cellular systems, all of which are displaced far from thermodynamic equilibrium. We conclude that non-equilibrium phase separation based upon jamming dynamics may provide a new physical picture to describe cellular migratory dynamics within and invasion from a tumor mass.TWO-SENTENCE SUMMARY Using a multicellular spheroid embedded within an engineered three-dimensional matrix, we show here the potential for coexistence of solid-like, fluid-like, and gas-like phases of the cellular collective described by a jamming phase diagram. Depending upon cell type and matrix density, moreover, invasion into matrix from the tumor periphery can switch from a continuous cellular collective that flows like a fluid to discrete cells that scatter individually like a gas.Competing Interest StatementThe authors have declared no competing interest. ER -