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Updated: May 2, 2026
Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
A local sympathetic-immune axis inhibits melanoma growth in mice by dictating adrenergic control
Tingting Liu1, Daniel Y Kutsovsky1, Ethan M Earlie2
1Department of Biochemistry and Biophysics, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
Abstract:
The nervous system drives tumor growth directly through intra-tumoral axons and indirectly through the systemic action of hormones. Yet contexts where the nervous system inhibits tumor growth are less defined. Here, we performed optical reconstruction of axonal innervation in mouse models of cutaneous melanoma, revealing progressive innervation by sympathetic axons. Local depletion of these axons accelerates while local optogenetic activation slows melanoma growth, together consistent with these axons acting as a physiological growth brake. The sympathetic nervous system is typically associated with driving tumor growth through activation of β-adrenergic receptors (ARs). Here, we find that the initial tumor seeding conditions sensitize melanomas from βAR-driven growth promotion toward α2-AR-driven growth inhibition. Mechanistically, the axonal activation of α2 ARs restricts the number and distribution of pro-tumor myeloid cells, independently of T cell activity. Together, our data reveal context-dependent, bidirectional neural control of tumor progression.
Insights
The nervous system can both promote and inhibit melanoma growth. Sympathetic axons act as a brake by activating alpha-2 adrenergic receptors, restricting pro-tumor myeloid cells.
Area of Science:
- Neuroscience
- Oncology
- Immunology
Background:
- The nervous system's role in cancer is complex, often promoting tumor growth.
- Contexts where the nervous system inhibits tumor progression are less understood.
- Sympathetic innervation is observed in various cancers, but its dual role is unclear.
Purpose of the Study:
- To investigate the role of sympathetic innervation in cutaneous melanoma growth.
- To determine the mechanisms by which the nervous system influences melanoma progression.
- To explore the context-dependent bidirectional neural control of tumor growth.
Main Methods:
- Optical reconstruction of axonal innervation in mouse melanoma models.
- Genetic depletion and optogenetic activation of sympathetic axons.
- Analysis of adrenergic receptor (AR) signaling pathways.
- Assessment of myeloid cell populations and T cell activity.
Main Results:
- Progressive sympathetic axonal innervation of cutaneous melanoma was observed.
- Depletion of sympathetic axons accelerated melanoma growth, while activation slowed it.
- Melanomas shifted from beta-AR driven growth promotion to alpha-2 AR driven inhibition.
- Alpha-2 AR activation restricted pro-tumor myeloid cells, independent of T cells.
Conclusions:
- Sympathetic axons can act as a physiological brake on melanoma growth.
- Melanoma progression is subject to context-dependent, bidirectional neural control.
- Alpha-2 AR signaling represents a novel mechanism for neural inhibition of tumor growth.
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