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A 3D Organotypic Melanoma Spheroid Skin Model
Published on: May 18, 2018
Melanoma to rhabdomyosarcoma plasticity in the setting of immunotherapy
Andrew D Knight1, Emily J Robitschek2, Jia-Ren Lin3
1Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, USA.
Background:
Acquired resistance to immune checkpoint inhibitors (ICIs) remains a significant challenge in the treatment of metastatic melanoma. Phenotypic plasticity, such as dedifferentiation and transdifferentiation, is an increasingly recognized mechanism of treatment resistance.
Methods:
We present a case of a 70-year-old man with metastatic melanoma who experienced progression through sequential treatments including pembrolizumab in combination with the HDAC inhibitor entinostat and ipilimumab. During treatment, a histologically distinct pleomorphic rhabdomyosarcoma (RMS) emerged at metastatic sites. Longitudinally acquired tumor samples representing both phenotypes were analyzed using whole-exome sequencing (WES), RNA sequencing (RNA-seq), and high-plex tissue imaging (spatial proteomics).
Findings:
WES revealed driver mutations (e.g., NRAS and NF1) and loss of heterozygosity (LOH) shared between phenotypes indicating a common ancestral clone. Phylogenetic analysis demonstrated an early divergence of the phenotypes, with each later acquiring unique mutations. RNA-seq showed mutually exclusive expression of lineage-specific markers as well as epithelial-mesenchymal transition and myogenic gene set enrichment in the RMS samples. High-plex imaging identified distinct tumor microenvironments, with RMS lesions enriched in CD163+ macrophages.
Conclusions:
This case provides molecular evidence of phenotypic plasticity occurring under the selective pressure of immune checkpoint inhibitor therapy.
Funding:
This study was supported by the National Institutes of Health (K12CA087723 and K08CA234458), the Doris Duke Charitable Foundation, and Adelson Medical Research Foundation.
Insights
This study shows that melanoma can change its cell type, becoming rhabdomyosarcoma, when treated with immune checkpoint inhibitors (ICIs). This phenotypic plasticity is a new mechanism of resistance to ICI therapy.
Area of Science:
- Oncology
- Cancer Biology
- Genetics
Background:
- Acquired resistance to immune checkpoint inhibitors (ICIs) is a major hurdle in metastatic melanoma treatment.
- Phenotypic plasticity, including dedifferentiation and transdifferentiation, is an emerging mechanism of treatment resistance.
Purpose of the Study:
- To investigate the molecular mechanisms of acquired resistance to ICIs in metastatic melanoma.
- To present a case study demonstrating phenotypic plasticity under ICI therapy.
Main Methods:
- Analyzed longitudinal tumor samples from a metastatic melanoma patient who progressed on ICIs.
- Utilized whole-exome sequencing (WES), RNA sequencing (RNA-seq), and high-plex tissue imaging (spatial proteomics).
Main Results:
- Identified shared driver mutations and loss of heterozygosity (LOH) between melanoma and emergent rhabdomyosarcoma (RMS) phenotypes, indicating a common origin.
- RNA-seq revealed distinct lineage-specific markers and enrichment of epithelial-mesenchymal transition and myogenic gene sets in RMS.
- Spatial proteomics showed distinct tumor microenvironments, with RMS lesions enriched in CD163+ macrophages.
Conclusions:
- This case provides molecular evidence of phenotypic plasticity in melanoma under the selective pressure of ICI therapy.
- Phenotypic plasticity represents a significant mechanism of acquired resistance to immune checkpoint inhibitors.
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