Abstract A confluent collective of epithelial cells lines every organ surface and body cavity. The epithelial collective typically remains quiescent and non-migratory while performing its routine barrier and immune functions, but becomes dynamic and migratory during embryonic development and airway morphogenesis, during airway repair and asthmatic airway remodeling, as well as during carcinoma invasion and metastasis. In these and other processes, the striking transition between non-migratory versus migratory behaviors is traditionally framed within the context of the epithelial-to-mesenchymal transition (EMT) or the partial EMT (pEMT). During pEMT the epithelial phenotype, which is said to be innately non-migratory, transitions toward a mesenchymal phenotype, which is innately migratory. But to initiate and sustain collective cellular migration, our central hypothesis holds that the EMT/pEMT mechanism as it is canonically defined is not obligatory. Rather, we propose that the newly discovered unjamming transition (UJT) mechanism in many cases elicits collective cellular migration and, importantly, can function independently of the EMT or pEMT. Unjamming is not to be mistaken for cellular migration or for remodeling. But unjamming does create the physical conditions that make cellular migration and remodeling possible. Using the confluent layer of primary human bronchial epithelial cells (HBECs) in air-liquid-interface (ALI) culture, here we propose to: 1) establish the UJT mechanism as an independent route to collective HBEC migration; 2) map in HBECs the molecular interactome of the UJT mechanism; and 3) explain molecular, structural, and migratory features that typify the UJT mechanism. Extensive preliminary data support the tenability of these aims, which are designed to illuminate basic mechanisms that differentiate UJT from EMT.

Project Narrative To migrate, it is widely presumed that the epithelial cell must first go through an epithelial-to-mesenchymal transition (EMT) or, more commonly, a partial EMT; this proposal argues, however, that our discovery of the cellular unjamming transition (UJT) reveals a powerful, unifying, and overriding biological principle that is distinct from the EMT mechanism but potentially is no less important. If true, we will have reframed a core concept in epithelial cell biology. Impact potentially spans development biology, wound repair, asthmatic airway remodeling, and metastatic disease.