DESCRIPTION (provided by applicant): Theoretical advances and experimental evidence from our laboratories now establish that migration of the constituent cell within the non-malignant epithelial cellular layer becomes dominated by physical interactions with nearest neighbors in a manner that is consistent with cell jamming. With changes of cellular crowding, cell-cell adhesion, or cooperative cellular propulsion, the confluent cellular collective can undergo a transition from a solid-like jammed phase in which cells become virtually frozen in place, to a fluid-like, unjammed phase in which cells readily exchange places and flow. The theory of critical scaling exponents predicts that the transition from solid-like jammed to fluid-lke unjammed phases is promoted by increased cell adhesive forces and linked to changes in cell shape. This theoretical prediction comprises our central hypothesis. Importantly, predictions from this theory are paradoxical to classical thinking but are borne out nevertheless by our preliminary data. Hence, this theory of cell jamming brings with it a new mechanism and a new physical picture of breast cancer cell migration. To test this theory, in Aim 1 we will characteriz jamming dynamics in a selected subset of the 9 breast cancer cell lines comprising the Bioresource Core Facility of the Physical Sciences-Oncology Network. In Aim 2 we will assess how cell-cell adhesion affects jamming with a specific focus on the changes in cellular adhesion that occur during the epithelial-to-mesenchymal transition (EMT). In Aim 3 we will investigate how the presence of cancer stem cells influence cellular jamming and collective motion. Impact: A key step in cancer progression is collective tumor cell migration, but how each individual cell coordinates its migration with that of immediate neighbors has defied mechanistic understanding. Here we propose experiments designed to unveil basic physics of collective cellular migration in early stages of tumor progression. Data derived from a comprehensive suite of experimental probes -cellular motions, traction forces, intercellular forces1,2,4,7-9 and cellular shapes- will be critically viewed through the lens of a novel theory of critical scaling.13,14 This theory of cell jamming is mechanistic, non-trivial, and counterintuitive. If supported by our data, it will not represent an incremental advance. Rather, it may provide important new insights concerning the physics of cancer progression, and, because its predictions are counterintuitive and paradoxical, it may lead to novel strategies for cancer treatment or prevention.

PUBLIC HEALTH RELEVANCE We have found previously that each cell within a cell cluster can become relatively free to move amongst its neighbors, or instead can get quite stuck and jammed. Do cells on one side of this jamming transition behave one way, and cells on the other side behave another way: jammed vs. fluidized, contained vs. invasive? Here we propose to answer this question in the context of early stages of breast tumor progression.