Charting metastasis
Source: Science Signaling, October 2022
Melanoma lesions are characterized by their heterogeneous cellular composition and contain melanoma cells that present as proliferative or invasive. Additional cell states contribute to a heterogeneous melanoma microenvironment. Karras et al. analyzed cellular heterogeneity in melanoma that functionally related to tumor growth and metastasis. scRNA-seq analysis of melanoma lesions identified malignant cells occupying seven distinct clusters, which included melanocytic (proliferative) and mesenchymal-like (invasive) populations. These clusters correlated with the progression of transcriptional programs seen in the differentiation of embryonic neural crest (NC) cells. Lineage tracing analysis of clonal populations indicated the presence of at least two groups arranged in a hierarchy in which a stem-like population led to a progenitor cell–like population. To test whether the clonal niches corresponded to the local microenvironment, spatial transcriptomics data were analyzed with scRNA-seq data. Pre-EMT (epithelial-to-mesenchymal transition) NC stem–like cells were more likely to be found in perivascular regions. In primary nodular human biopsies, pre-EMT NC stem–like cells were found in proximity to blood vessels. Melanoma cells co-cultured with endothelial cells (ECs) gave rise to cells with dedifferentiated NC-like and pre-EMT NC stem–like signatures, suggesting that ECs promote melanoma dedifferentiation and growth. PRRX1 (paired related homeobox 1) promotes EMT in epithelial cancers, and its silencing in mesenchymal-like melanoma cultures decreased mesenchymal and EMT signatures and ability to invade. Fate mapping of Prrx1+ cells in vivo showed that they were not responsible for the growth of primary tumors but were prominent among metastatic tumor cells. In a longitudinal study, metastatic Prrx1+ cells transitioned from high to low expression of the mesenchymal-like/EMT signature, suggesting that Prrx1 marks a population that initiates metastasis and subsequently undergoes MET. These findings shed light on the complexity and organization of melanoma differentiation and the microenvironmental influence on the acquisition of invasive characteristics by melanoma cells.