Tumor invasion as non-equilibrium phase separation
Wenying Kang, Jacopo Ferruzzi, Catalina-Paula Spatarelu, Yu Long Han, Yasha Sharma, Stephan Koehler, James P. Butler, Darren Roblyer, Muhammad H. Zaman, Ming Guo, Zi Chen, Adrian F. Pegoraro, Jeffrey J. Fredberg
Received Date: 10th April 20
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.
Read in full at bioRxiv.
This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.