During tumor progression, cancer cells come into contact with various non-tumor cell types, but it is unclear how tumors adapt to these new environments. Here, we integrate spatially resolved transcriptomics, single-cell RNA-seq, and single-nucleus RNA-seq to characterize tumor-microenvironment interactions at the tumor boundary. Using a zebrafish model of melanoma, we identify a distinct “interface” cell state where the tumor contacts neighboring tissues. This interface is composed of specialized tumor and microenvironment cells that upregulate a common set of cilia genes, and cilia proteins are enriched only where the tumor contacts the microenvironment. Cilia gene expression is regulated by ETS-family transcription factors, which normally act to suppress cilia genes outside of the interface. A cilia-enriched interface is conserved in human patient samples, suggesting it is a conserved feature of human melanoma. Our results demonstrate the power of spatially resolved transcriptomics in uncovering mechanisms that allow tumors to adapt to new environments.
Chromatin state and oncogenic competence
Although specific DNA mutations can lead to tumor generation, they are not transforming in all cellular contexts. This may be due to the intrinsic transcriptional program present in the cell of origin. Using zebrafish and human pluripotent stem cell cancer models, Baggiolini
et al
. report that neural crest cells and melanoblasts (precursors to melanocytes) are susceptible to specific mutation of the
BRAF
gene, whereas melanocytes are relatively resistant (see the Perspective by Vredevoogd and Peeper). The competent cells display higher levels of chromatin factors such as the protein ATAD2 compared with the less competent ones. ATAD2 forms a complex with the neural crest transcription factor SOX10 and establishes a chromatin state that makes them permissive to BRAF mutagenesis. These data indicate that developmental chromatin programs are a determinant of how cells respond to DNA mutations. —BAP
Highlights d Melanomas exhibit 3 cell states: neural-crest, mature melanocyte, and stress-like d The stress-like cancer cell state is conserved across tumor types and species d Stress-like cancer cells are pro-tumorigenic and efficient at seeding new tumors d Stress-like cancer cells hold drug-resistant properties induced by heat shock
Clathrin, dynamin, and ARF6 accumulate around wounds in Drosophila embryos in a calcium- and actomyosin-dependent manner and drive polarized E-cadherin endocytosis, which is necessary for actomyosin remodeling during wound repair.
Graphical AbstractHighlights d Wound-induced ROS production promotes healing in Drosophila and zebrafish embryos d ROS direct redistribution of junctions and the cytoskeleton at the wound margin d Src oxidation contributes to E-cadherin and myosin polarization around wounds
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