Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq

TLDR

The study aimed to dissect melanoma tumor heterogeneity by applying single‑cell RNA‑sequencing to 4,645 cells from 19 patients. The authors performed single‑cell RNA‑seq on these cells, profiling malignant, immune, stromal, and endothelial populations. The analysis uncovered transcriptionally heterogeneous malignant cells with distinct MITF‑high and MITF‑low/AXL‑high states, spatially and cell‑cycle‑dependent drug‑resistance programs, diverse tumor‑microenvironment interactions, and variable T‑cell exhaustion and clonal expansion, highlighting the complex cellular ecosystem and therapeutic implications.

Abstract

To explore the distinct genotypic and phenotypic states of melanoma tumors, we applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, and endothelial cells. Malignant cells within the same tumor displayed transcriptional heterogeneity associated with the cell cycle, spatial context, and a drug-resistance program. In particular, all tumors harbored malignant cells from two distinct transcriptional cell states, such that tumors characterized by high levels of the MITF transcription factor also contained cells with low MITF and elevated levels of the AXL kinase. Single-cell analyses suggested distinct tumor microenvironmental patterns, including cell-to-cell interactions. Analysis of tumor-infiltrating T cells revealed exhaustion programs, their connection to T cell activation and clonal expansion, and their variability across patients. Overall, we begin to unravel the cellular ecosystem of tumors and how single-cell genomics offers insights with implications for both targeted and immune therapies.