Non-Metastatic Cutaneous Melanoma Induces Chronodisruption in Central and Peripheral Circadian Clocks

Area of Science:

• Chronobiology
• Cancer Biology
• Molecular Oncology

Background:

• The biological clock regulates homeostasis, and its disruption is linked to cancer.
• The role of the biological clock in melanoma, particularly its interaction with the tumor microenvironment (TME) and macro-environment (TMaE), remains largely unknown.

Purpose of the Study:

• To investigate the impact of a non-metastatic melanoma tumor on the biological clock within the TME and TMaE.
• To identify specific molecular clock-related gene expression changes in response to melanoma.

Main Methods:

• Utilized a murine B16-F10 melanoma model in C57BL/6J mice.
• Collected samples from tumor-adjacent skin, tumor tissue, lungs, liver, and suprachiasmatic nucleus (SCN) at 6-hour intervals over 24 hours.
• Analyzed gene expression patterns related to circadian rhythms, light/thermo-reception, proliferation, melanogenesis, and DNA repair.

Main Results:

• Localized melanoma significantly impaired the biological clock in adjacent skin, altering gene expression.
• The tumor's molecular clock showed reduced but still oscillatory expression compared to healthy skin.
• Distant organs, including lungs, liver, and the SCN, exhibited significant chronodisruption due to tumor presence.
• Gene expression clustering allowed differentiation between primary melanoma and healthy skin.

Conclusions:

• Non-metastatic melanoma disrupts biological clocks across multiple organs, indicating systemic chronodisruption.
• Alterations in the TME and TMaE molecular clocks may influence melanoma development, progression, and metastasis.
• The molecular clock presents a promising pharmacological target for melanoma treatment.