Reciprocal interactions between EMT and BMP signalling drive collective cell invasion

During collective cell invasion, epithelial-to-mesenchymal transition (EMT) and morphogen signalling-mediated cell fate specification are traditionally viewed as a linear cascade: morphogens drive cell fates that activate EMT programs. Here, we uncover reciprocal coupling between EMT initiation and BMP signalling mediated by SNAI2 and SMAD1. Using substrate-induced EMT in ex vivo explants, we demonstrate that EMT initiation upregulates SMAD1 expression, priming cells for BMP signalling competence across germ layers. Single-cell RNA sequencing reveals SNAI2 and SMAD1 co-expression in EMT initiation regions, and SNAI2 overexpression is sufficient to induce ectopic SMAD1 expression in vivo. While BMP signalling is dispensable for EMT initiation, it regulates cell fate proportions, dispersal dynamics, precursor region depletion rates, and migration directionality. This coupling provides a mechanism for synchronising cell fate specification with invasion progression during axis elongation, positioning EMT as a process that actively modulates morphogen competence to coordinate tissue-level cell behaviours during collective cell invasion. Overall design: Bulk RNA sequencing of APS and PNP explants before (0h) and after (24h) migration on human fibronectin-coated glass. Sample names have been re-named since the experiment: MSP is APS_0h, MSP_EXPLANT is APS_24h, NP is PNP_0h, and NP_EXPLANT is PNP_24h.