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Updated: Jun 12, 2025
A Melanoma Patient-Derived Xenograft Model
Published on: May 20, 2019
Treatment resistance to melanoma therapeutics on a single cell level
Lijun Yao1,2, Bradley A Krasnick3, Ye Bi3
1Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA.
Abstract:
Therapy targeting the BRAF-MEK cascade created a treatment revolution for patients with BRAF mutant advanced melanoma. Unfortunately, 80% patients treated will progress by 5 years follow-up. Thus, it is imperative we study mechanisms of melanoma progression and therapeutic resistance. We created a scRNA (single cell RNA) atlas of 128,230 cells from 18 tumors across the treatment spectrum, discovering melanoma cells clustered strongly by transcriptome profiles of patients of origins. Our cell-level investigation revealed gains of 1q and 7q as likely early clonal events in metastatic melanomas. By comparing patient tumors and their derivative cell lines, we observed that PD1 responsive tumor fraction disappears when cells are propagated in vitro. We further established three anti-BRAF-MEK treatment resistant cell lines using three BRAF mutant tumors. ALDOA and PGK1 were found to be highly expressed in treatment resistant cell populations and metformin was effective in targeting the resistant cells. Our study suggests that the investigation of patient tumors and their derivative lines is essential for understanding disease progression, treatment response and resistance.
Insights
Researchers studied melanoma progression and resistance to BRAF-MEK targeted therapy using a single-cell RNA atlas. They identified ALDOA and PGK1 as key targets in resistant cells, suggesting metformin as a potential treatment.
Area of Science:
- Oncology
- Genomics
- Translational Medicine
Background:
- BRAF-MEK targeted therapy revolutionized advanced melanoma treatment.
- However, most patients (80%) experience disease progression within 5 years.
- Understanding melanoma progression and therapeutic resistance is crucial.
Purpose of the Study:
- To investigate mechanisms of melanoma progression and therapeutic resistance.
- To create a comprehensive single-cell RNA atlas of melanoma tumors across the treatment spectrum.
- To identify novel therapeutic targets for treatment-resistant melanoma.
Main Methods:
- Generated a single-cell RNA (scRNA) atlas of 128,230 cells from 18 patient tumors.
- Analyzed transcriptome profiles to understand cellular heterogeneity and origins.
- Established anti-BRAF-MEK treatment-resistant cell lines from patient tumors.
- Investigated gene expression in resistant populations and tested metformin efficacy.
Main Results:
- Melanoma cells clustered by patient origin transcriptome profiles.
- Gains of 1q and 7q were identified as potential early clonal events in metastatic melanoma.
- PD1-responsive tumor fractions were lost in vitro propagation.
- ALDOA and PGK1 were highly expressed in treatment-resistant cells.
- Metformin demonstrated efficacy against resistant melanoma cells.
Conclusions:
- Single-cell analysis of patient tumors and derivative cell lines is essential for understanding melanoma.
- Identifying mechanisms of resistance can guide the development of more effective therapies.
- Targeting ALDOA and PGK1 with metformin shows promise for overcoming BRAF-MEK inhibitor resistance.
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