# Biopsy RNA-seq captures TROP-2–linked migration and clonal resistance to forecast aggressiveness in metastatic melanoma

## TL;DR

This study identifies a dormant state in melanoma cells linked to TROP2, which may help predict tumor aggressiveness and treatment resistance.

## Contribution

The study introduces a dormancy score based on an eight-gene signature to stratify melanoma tumors and highlights TROP2 as a potential biomarker.

## Key findings

- A dormancy score based on an eight-gene signature stratifies tumors along a dormancy–proliferation axis and correlates with clinical outcomes.
- TROP2 is upregulated in the dormant state and marks a rare subpopulation of therapy-resistant melanoma cells.
- TROP2 expression is predominantly intracellular in the dormant phenotype, suggesting a role in tumor resistance.

## Abstract

Unlike many other solid tumors, melanoma cells possess a remarkable ability to dynamically transition between distinct transcriptional states in response to environmental cues or therapeutic pressure. Among the adaptive mechanisms underlying this plasticity, the epithelial-to-mesenchymal transition (EMT) has garnered increasing attention, as it facilitates the shift from a proliferative, epithelial-like phenotype to a more invasive, mesenchymal-like phenotype frequently associated with cellular dormancy, quiescence and resistance to therapy. Despite growing interest in this phenomenon, the characterization of dormant cellular phenotypes and their clinical significance remains incomplete.

In this study, we adopted a comprehensive approach integrating patient-derived melanoma cell lines, bulk RNA sequencing from tumor biopsies and analysis of independent bulk and single-cell public datasets. This multi-dimensional strategy enabled the identification of a reproducible dichotomy between “proliferative” and “dormant” phenotypes, characterized by distinct levels of mitotic activity and mesenchymal gene expression profiles. By leveraging an eight-gene transcriptional signature, we constructed a “dormancy score” able to stratify tumors along a dormancy–proliferation axis, revealing strong associations with clinical outcomes such as progression-free survival (PFS), overall survival (OS) and response to immunotherapy.

Within the dormant-associated gene module, the surface glycoprotein TACSTD2 (TROP2) emerged as a central hub gene. TROP2 expression was consistently upregulated in the dormant-like transcriptional state. Supporting these findings, single-cell RNA sequencing data confirmed that TROP2 marks a rare subpopulation of malignant cells that may constitute a quiescent, therapy-resistant niche. Besides, results highlight a predominant intracellular expression of TROP2 in the dormant phenotype.

Together, these findings define a robust dormant phenotype in melanoma with both molecular and clinical significance and evaluate TROP2 as a potential biomarker and therapeutic target for identifying and eradicating dormant and treatment-refractory tumor cells.

The online version contains supplementary material available at 10.1186/s13046-026-03646-1.