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Updated: May 9, 2026
A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
The dioxin receptor has tumor suppressor activity in melanoma growth and metastasis
María Contador-Troca1, Alberto Alvarez-Barrientos, Eva Barrasa
1Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias and.
Abstract:
Melanoma is a highly metastatic and malignant skin cancer having poor rates of patient survival. Since the incidence of melanoma is steadily increasing in the population, finding prognostic and therapeutic targets are crucial tasks in cancer. The dioxin receptor (AhR) is required for xenobiotic-induced toxicity and carcinogenesis and for cell physiology and organ homeostasis. Yet, the mechanisms by which AhR affects tumor growth and dissemination are largely uncharacterized. We report here that AhR contributes to the tumor-stroma interaction, blocking melanoma growth and metastasis when expressed in the tumor cell but supporting melanoma when expressed in the stroma. B16F10 cells engineered to lack AhR (small hairpin RNA for AhR) exacerbated melanoma primary tumorigenesis and lung metastasis when injected in AhR+/+ recipient mice but not when injected in AhR- /- mice or when co-injected with AhR-/- fibroblasts in an AhR+/+ stroma. Contrary, B16F10 cells expressing a constitutively active AhR had reduced tumorigenicity and invasiveness in either AhR genetic background. The tumor suppressor role of AhR in melanoma cells correlated with reduced migration and invasion, with lower numbers of cancer stem-like cells and with altered levels of β1-integrin and caveolin1. Human melanoma cell lines with highest AHR expression also had lowest migration and invasion. Moreover, AHR expression was reduced in human melanomas with respect to nevi lesions. We conclude that AhR knockdown in melanoma cells requires stromal AhR for maximal tumor progression and metastasis. Thus, AhR can be a molecular marker in melanoma and its activity in both tumor and stromal compartments should be considered.
Insights
The dioxin receptor (AhR) acts as a tumor suppressor in melanoma cells, inhibiting growth and metastasis. However, AhR in the tumor stroma promotes melanoma progression, highlighting its dual role.
Area of Science:
- Oncology
- Molecular Biology
- Dermatology
Background:
- Melanoma incidence is rising, necessitating new prognostic and therapeutic targets.
- The dioxin receptor (AhR) plays roles in toxicity, carcinogenesis, and homeostasis, but its function in melanoma is unclear.
Purpose of the Study:
- To investigate the role of the dioxin receptor (AhR) in melanoma tumor growth and metastasis.
- To elucidate the mechanisms by which AhR influences tumor-stroma interactions in melanoma.
Main Methods:
- Engineered B16F10 melanoma cells with and without AhR expression (using small hairpin RNA).
- Injected engineered cells into recipient mice with different AhR genetic backgrounds.
- Co-injected cells with AhR-deficient fibroblasts.
- Analyzed tumor growth, metastasis, cell migration, invasion, cancer stem-like cells, and protein levels (β1-integrin, caveolin1).
- Examined AHR expression in human melanoma and nevus lesions.
Main Results:
- AhR deficiency in melanoma cells exacerbated primary tumor growth and metastasis in an AhR+/+ stroma.
- Melanoma cells expressing constitutively active AhR showed reduced tumorigenicity and invasiveness.
- Tumor suppressor role of AhR in melanoma cells correlated with reduced migration, invasion, and cancer stem-like cells.
- Human melanoma cells with high AHR expression exhibited lower migration and invasion.
- AHR expression was reduced in human melanomas compared to nevi.
Conclusions:
- AhR acts as a tumor suppressor in melanoma cells, inhibiting proliferation and metastasis.
- Stromal AhR is required for maximal tumor progression and metastasis when melanoma cells have reduced AhR.
- AhR's activity in both tumor and stromal compartments is critical and suggests AhR as a potential prognostic marker.
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