Defining and exploiting therapeutically the role of nociceptor neuron–tumor–pericyte axis that drives melanoma progression via CGRP-RAMP1 signaling

About This Grant

PROJECT SUMMARY The overall objective of this study is to understand how nociceptor neuron-tumor-pericyte axis formed within the melanoma metastatic microenvironment regulates disease progression. Melanoma is the most lethal form of skin cancer due to its tendency to rapidly metastasize. Current therapeutic approaches are often insufficient to achieve durable responses. Thus, efforts to identify novel therapeutic targets are urgently needed to overcome resistance, slowing or preventing disease progression. Recent reports from my laboratory and others show that cancer and the nervous system bear a close, entangled relationship within the tumor microenvironment. Our unpublished data finds that nociceptor neurons penetrate metastatic melanoma microenvironment, increasing in density with disease progression. Nevertheless, the role of peripheral nociceptor neurons in metastatic melanoma advancement remains completely unknown. Our preliminary studies show that nociceptor denervation or silencing decreases melanoma metastatic outgrowth. Nociceptor neurons communicate with other cell types through biologically active neuropeptides released from their endings; CGRP is the most abundant of these neuropeptides. High mRNA expressions of CALCA (which encodes CGRP) and of the CGRP receptor subunit (RAMP1) are associated with increased risk of death in patients with metastatic melanoma. Our single-cell RNA-seq data analysis from human secondary melanoma sites shows that RAMP1 is highly expressed specifically in malignant cells and pericytes. RAMP1 knockdown or pharmacologic blockade in melanoma cells in vitro decreases their migratory and growth capacities induced by CGRP, while pharmacologic blockade of CGRP-induced RAMP1 signaling inhibits pericytes’ proliferation and angiogenic capacities in vitro. Moreover, treatment with a RAMP1 antagonist, Rimegepant, FDA-approved for migraine, in vivo decreases lung melanoma nodules. These findings lead to this proposal to understand the mechanisms through which nociceptor neurons via RAMP1 signaling impact melanoma progression. We hypothesize that RAMP1 expression in malignant cells and pericytes within metastatic melanoma accelerates disease advancement, while its inhibition will slow melanoma progression. Thus, we will test this hypothesis using two Specific Aims to identify the cell-type specific role of CGRP-RAMP1 signaling that drives melanoma metastasis in vivo (Aim 1) and exploit therapeutically and determine the clinical significance of CGRP-RAMP1 signaling in melanoma metastases (Aim 2). Overall, our study will reveal the mechanistic and therapeutic significance of RAMP1 signaling in melanoma progression. This can ultimately lead to the identification of novel strategies for the clinical management of advanced melanoma and provide a rationale for clinically testing drugs that will modulate RAMP1 signaling to obtain superior and lasting anti-melanoma responses. The use of murine models is strictly necessary because neither in vitro nor in silico methodologies can adequately replicate the complex in vivo interactions between the host sensory nervous system and melanoma metastases required to evaluate novel targeted therapeutics.