Defining the Factors that Regulate the Conversion to a Trailblazer Epithelial to Mesenchymal Transition State

Abstract

Tumor heterogeneity resulting from the co-existence of phenotypically diverse tumor cellpopulations is a major contributor in the pathogenesis of several human malignancies. In addition to the steady acquisition of heritable molecular changes during cancer progression, cellular plasticity contributes to phenotypic modifications that often allow cells to sustain both a migratory and proliferative character. A critical example of cell plasticity is the epithelial-to- mesenchymal transition (EMT) where cancer cells convert across a spectrum of epithelial and mesenchymal cellular identities. Multiple distinct EMT states have been described and their associated regulatory mechanisms have begun to be defined. Such is the case of the trailblazer and opportunist EMT states. Trailblazer EMT activation confers cells with ability to extend cellular protrusions, which reorganize the ECM into paths that facilitate invasion. Importantly, the paths created by trailblazer cells promote the invasion of siblings in an opportunist EMT state, which confers cells with migratory ability, but not the capacity to independently initiate invasion. Notably, this relationship permits opportunist cells to convert from a benign to a malignant invasive state. The data presented here suggests that cell-intrinsic properties influence the response to extrinsic EMT-inducing factors and the acquisition of trailblazer cell features. Specifically, our findings reveal that the intrinsic expression of the AP-1 family member Fra1 is required for the induction of a trailblazer EMT by TGFb. Moreover, we uncovered that the TGFb and EGFR-ERK1/2-Fra1 signaling pathways activate distinct regulatory networks that increase collective invasion. Importantly, Fra1 primes cancer cells to rapidly invade in response to TGFb while retaining epithelial traits. Given these observations, I propose that Fra1 is a priming factor that allows cells to respond to TGFb, undergo a trailblazer EMT and lead collective invasion. Therefore, integration of parallel signaling programs dictates the mode of invasion, promoting increased cancer cell heterogeneity in basal-like breast tumors.