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Updated: Jun 25, 2025
A Melanoma Patient-Derived Xenograft Model
Published on: May 20, 2019
Modeling Melanoma Heterogeneity In Vitro: Redox, Resistance and Pigmentation Profiles
Larissa Anastacio da Costa Carvalho1,2, Isabella Harumi Yonehara Noma2, Adriana Hiromi Uehara2
1Department of Tumor Biology, Moffitt Cancer Center, Tampa, FL 33612, USA.
Abstract:
Microenvironment and transcriptional plasticity generate subpopulations within the tumor, and the use of BRAF inhibitors (BRAFis) contributes to the rise and selection of resistant clones. We stochastically isolated subpopulations (C1, C2, and C3) from naïve melanoma and found that the clones demonstrated distinct morphology, phenotypic, and functional profiles: C1 was less proliferative, more migratory and invasive, less sensitive to BRAFis, less dependent on OXPHOS, more sensitive to oxidative stress, and less pigmented; C2 was more proliferative, less migratory and invasive, more sensitive to BRAFis, less sensitive to oxidative stress, and more pigmented; and C3 was less proliferative, more migratory and invasive, less sensitive to BRAFis, more dependent on OXPHOS, more sensitive to oxidative stress, and more pigmented. Hydrogen peroxide plays a central role in oxidative stress and cell signaling, and PRDXs are one of its main consumers. The intrinsically resistant C1 and C3 clones had lower MITF, PGC-1α, and PRDX1 expression, while C1 had higher AXL and decreased pigmentation markers, linking PRDX1 to clonal heterogeneity and resistance. PRDX2 is depleted in acquired BRAFi-resistant cells and acts as a redox sensor. Our results illustrate that decreased pigmentation markers are related to therapy resistance and decreased antioxidant defense.
Insights
Melanoma subpopulations exhibit distinct traits influencing BRAF inhibitor resistance. Decreased pigmentation and antioxidant defenses, like PRDX1, are linked to therapy resistance in resistant clones.
Area of Science:
- Oncology
- Cancer Biology
- Melanoma Research
Background:
- Tumor microenvironments drive transcriptional plasticity, leading to subpopulations.
- BRAF inhibitors (BRAFis) can select for resistant melanoma clones.
Purpose of the Study:
- To investigate the distinct characteristics of melanoma subpopulations.
- To explore the mechanisms of BRAF inhibitor resistance.
Main Methods:
- Stochastic isolation of three distinct melanoma subpopulations (C1, C2, C3).
- Analysis of morphology, phenotype, function, and gene expression.
- Assessment of sensitivity to BRAF inhibitors and oxidative stress.
Main Results:
- Clones C1 and C3 showed reduced proliferation, increased invasion, and BRAFi resistance.
- Lower expression of MITF, PGC-1α, and PRDX1 was observed in resistant clones (C1, C3).
- Decreased pigmentation markers correlated with therapy resistance and reduced antioxidant defense.
Conclusions:
- Melanoma clonal heterogeneity contributes to BRAF inhibitor resistance.
- PRDX1 expression is linked to clonal heterogeneity and resistance.
- Reduced pigmentation and antioxidant capacity are indicators of therapy resistance.
