Exploring the landscape of tumor invasion at single-cell resolution

When tumors invade into different tissues, they come into contact with new cell types within the tumor microenvironment, but it is unclear how tumor and microenvironment cells interact to facilitate tumor invasion. To understand how changes in gene expression in both the tumor and surrounding cells influence tumor invasion, we integrated spatial transcriptomics, single-cell RNA-seq, and in vivo confocal microscopy to characterize tumor-microenvironment cell-cell interactions in a transgenic zebrafish model of melanoma. Using spatial transcriptomics, we identified a unique “interface” cell state at the tumor/microenvironment boundary. Single-cell RNA-seq revealed that the interface is composed of specialized tumor and microenvironment cells that upregulate a common set of cilia genes. We further found that cilia proteins are polarized specifically where the tumor contacts the microenvironment, indicating a novel role for cilia in melanoma invasion. Motif analysis revealed that cilia gene expression in interface cells is regulated by ETS-family transcription factors, which normally act to suppress cilia genes outside of the interface. Finally, we found that an ETS/cilia-driven interface is conserved across ten patient samples, indicating that it is a conserved feature of human melanoma. We are currently investigating the molecular mechanisms by which cilia facilitate tumor progression. Our results uncover a previously unknown role for cilia in melanoma invasion, and the power of applying interdisciplinary approaches to understanding cancer cell biology.