Related Experiment Video
Updated: May 23, 2026
Minimally Invasive Isolated Limb Perfusion (MI-ILP) for Locally Advanced Melanomas and Sarcomas of the Extremity
Published on: January 31, 2025
Gene expression changes in melanoma metastases in response to high-dose chemotherapy during isolated limb perfusion
Jasper Wouters1, Marguerite Stas, Olivier Govaere
1Translational Cell & Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium. jasper.wouters@med.kuleuven.be
Abstract:
Despite recent advances in melanoma therapy, disseminated melanoma still lacks effective treatment, and recurrence of the tumor frequently occurs, even after high-dose chemotherapy. The mechanisms responsible for this chemoresistance or for the formation of new relapses remain poorly understood. Using a human 'model', in which the isolated limb is perfused with high doses of the chemotherapeutic melphalan (ILP), we identified a five-gene set (ATF3, CYR61, IER5, IL6, and PTGS2) of stress-induced genes that was consistently upregulated after ILP in all in-transit metastatic melanoma samples as well as in three melphalan-treated melanoma cell lines. Early post-ILP relapses retained these elevated expressions, whereas the expression of these genes returned to their original levels in late post-ILP recurrences. In addition, we identified upregulation of these genes in the A375 cell line's side population (SP) and melanospheres, established methods to enrich for candidate cancer stem cells (CSCs), which are considered chemoresistant and tumorigenic, and thus proposed to be responsible for tumor relapse. Our data identify an immediate and short-term upregulation of early stress-responsive genes that are potentially linked to chemoresistance and CSCs.
Insights
Researchers identified five stress-induced genes upregulated after melphalan treatment in melanoma. These genes may be linked to chemoresistance and tumor relapse, particularly in early recurrences and candidate cancer stem cells.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Disseminated melanoma remains difficult to treat, with frequent recurrence even after chemotherapy.
- Mechanisms underlying chemoresistance and tumor relapse in melanoma are not well understood.
Purpose of the Study:
- To identify genes associated with chemoresistance and relapse in melanoma.
- To investigate the role of stress-induced genes and cancer stem cells (CSCs) in melanoma treatment failure.
Main Methods:
- Utilized an isolated limb perfusion (ILP) model with high-dose melphalan in human melanoma samples.
- Analyzed gene expression of stress-induced genes (ATF3, CYR61, IER5, IL6, PTGS2) in melanoma samples and cell lines.
- Investigated gene expression in side population (SP) cells and melanospheres, enriched for candidate CSCs.
Main Results:
- A set of five stress-induced genes was consistently upregulated after ILP in melanoma samples and cell lines.
- Elevated gene expression persisted in early post-ILP relapses but returned to baseline in late recurrences.
- Upregulation of these genes was observed in CSC-enriched populations (SP and melanospheres).
Conclusions:
- Immediate, short-term upregulation of specific stress-responsive genes is linked to melphalan treatment in melanoma.
- These genes are potentially involved in chemoresistance and the maintenance of cancer stem cells, contributing to tumor relapse.
