Defining and exploiting therapeutically the role of the neuropeptide receptor PAC1 in tumor-infiltrating pericytes that drives melanoma progression.

The overall objective of this study is to understand and exploit therapeutically the role of neuropeptide receptor PAC1 in melanoma-infiltrating pericytes during melanoma progression. Melanoma is the most lethal form of skin cancer due to its tendency to rapidly metastasize, and current therapies often do not achieve durable responses. Novel molecular targets are urgently needed to develop more effective treatments. Obtaining a better understanding of the interplay between various cells and systems within the tumor microenvironment will identify potential new targets for therapeutic intervention. Recent reports from my laboratory and others show that cancer and the nervous system bear a close, entangled relationship. Melanoma-infiltrating neurons are an integral component of the tumor microenvironment, and manipulation of these innervations affect cancer progression, but the mechanisms underlying these findings remain poorly understood. Neurons signal to other cell types via neuropeptides binding to neuropeptide receptors. We identified ADCYAP1 and ADCYAP1R1, which encode the pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor PAC1, as the genes most significantly associated with increased risk of death in patients with melanoma. We found that PACAP+ neurons infiltrate within the melanoma microenvironment and increase in density with disease progression in vivo. Our preliminary data showed that chemogenetic silencing of PACAP+ neurons decreased tumor growth and pulmonary melanoma metastases, while intra-tumoral PACAP injection accelerated melanoma advancement. Single-cell RNA-seq data combined with immunohistochemistry and flow cytometry indicate that PAC1 expression is specific to pericytes, suggesting a potential role in pericyte function during melanoma progression. Our pilot data show that targeting PAC1 in pericytes, either through genetic deletion or a selective blockade, slows melanoma development and pulmonary metastatic outgrowth. This highlights the importance of understanding the mechanisms by which PACAP-PAC1 signaling in melanoma-infiltrating pericytes impacts melanoma growth and metastasis, in hopes of laying the foundation for the development of new therapeutic strategies. We hypothesize that PAC1 expression in tumor-infiltrating pericytes accelerates melanoma progression by inducing a pro-tumorigenic microenvironment. We will test this hypothesis using two Specific Aims: 1) Identify the role of PAC1 signaling in melanoma-infiltrating pericytes that drives melanoma progression in vivo and 2) Exploit therapeutically the neuropeptide receptor PAC1 in melanoma and determine PAC1 protein expression clinical significance. To our knowledge, the proposed work is the first to investigate the hypothesis that cancer-infiltrating pericytes are regulated by the nervous system. Overall, successful completion of our planned pre-clinical studies will reveal the mechanistic significance of the expression of the neuropeptide receptor PAC1 in melanoma. This can ultimately provide a rationale for clinically testing drugs that will modulate PAC1 signaling to obtain superior and lasting anti-melanoma responses. Project Number: 1R37CA300434-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Alexander Birbrair | Institution: UNIVERSITY OF WISCONSIN-MADISON, MADISON, WI | Award Amount: $508,651 | Activity Code: R37 | Study Section: Tumor Host Interactions Study Section[THI] View on NIH RePORTER: https://reporter.nih.gov/project-details/11297383