DNp63-regulated epithelial-to-mesenchymal transition state heterogeneity confers a leader-follower relationship that drives collective invasion

Defining how interactions between tumor subpopulations contribute to invasion is essential for understanding how tumors metastasize. Here, we find that the heterogeneous expression of the transcription factor DNp63 confers distinct proliferative and invasive epithelial-to-mesenchymal transition (EMT) states in subpopulations that establish a leader-follower relationship to collectively invade. A DNp63-high EMT program coupled the ability to proliferate with an IL1a- and miR-205-dependent suppression of cellular protrusions that are required to initiate collective invasion. An alternative DNp63-low EMT program conferred cells with the ability to initiate and lead collective invasion. However, this DNp63-low EMT state triggered a collateral loss of fitness. Importantly, rare growth-suppressed DNp63-low EMT cells influenced tumor progression by leading the invasion of proliferative DNp63-high EMT cells in heterogeneous primary tumors. Thus, heterogeneous activation of distinct EMT programs promotes a mode of collective invasion that overcomes cell intrinsic phenotypic deficiencies to induce the dissemination of proliferative tumor cells.