Axonal Control of Tumor Progression

/ Abstract Melanoma is a striking example of a cancer where a subset of patients are effectively treated, while others are resistant to the same therapies or develop resistance after an initial positive response. This resistance underscores the unmet need to develop new therapies and new strategies to potentiate existing therapies. Inter- cellular interactions with the melanoma microenvironment control tumor initiation and progression and are widely considered critical to the efficacy of chemotherapies and immunotherapies. Axons, the cable-like projections that connect neurons with their target cells, are a newly discovered component of many tumor microenvironments, including amongst melanomas. However, how the nervous system signals within melanomas and the cells within the melanoma microenvironment that they target are largely unknown, critical prerequisites to determining whether axons are viable therapeutic targets. Our project is focused on defining how axons of the sympathetic nervous system inhibit melanoma growth, focused on interactions between these axons and immune effectors. Sympathetic axons release the neurotransmitter norepinephrine that activates adrenergic receptors on target cells. Our first goal is to define the cell types in the melanoma microenvironment that express these receptors and, through genetic analysis, their functional requirement for these receptors for axonal inhibition of melanoma growth. Here, our specific focus is on adrenergic receptors in myeloid derived cells including macrophages as part of our broader hypothesis that macrophages are critical effectors of sympathetic nerve-derived inhibitory signals (Aim 1). Next, we will focus on the anti-tumor immune response that sympathetic axons initiate. We will determine the degree to which intra-tumoral axons are susceptible to and protected from inflammatory damage that may limit their capacity to effectively signal to their targets as tumors grow (Aim 2). These experiments are aided by our ability to perform whole tumor imaging and to reconstruct and quantify the tumor-wide axonal innervation patterns. Finally, we will test whether stimulation of sympathetic axons or the adrenergic receptors that they activate reduces melanoma progression either alone or in combination with established anti-melanoma therapies such as immune checkpoint blockade (Aim 3). Insights from our studies are expected to inform new anti-melanoma strategies that harness the immune-regulatory function of intra-tumoral sympathetic axons. Project Number: 1R01CA311807-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: David Simon | Institution: WEILL MEDICAL COLL OF CORNELL UNIV, NEW YORK, NY | Award Amount: $694,133 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 BTC-Y (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11343358