Deciphering the role of cancer pain-associated neuronal activity in driving malignancies - PROJECT SUMMARY Recent paradigm-shifting discoveries demonstrated that neurons are critical drivers of malignancies (cancer), leading to clinical trials to test neuromodulatory drugs in cancer patients. Many types of cancer are associated with severe pain which indicates sensory neuron hyperactivity, raising the intriguing possibility that cancer pain- associated sensory neuron activity accelerates cancer progression. Our long-term objective is to understand the role of neuronal activity in cancer pathophysiology and identify therapeutic targets to improve cancer patient survival and quality of life. Leveraging preclinical models of malignant peripheral nerve sheath tumor (MPNST), where the neoplasm develops within peripheral nerves, our preliminary data reveal that MPNST cells induce sensory neuron hyperactivity and pain, and that sensory neuron activity accelerates tumor growth. Based on these findings, our central hypothesis is that a feedforward mechanism exists between cancer pain-associated sensory neuron hyperactivity and MPNST growth. We will address the hypothesis by uncovering how MPNST cells activate sensory neurons to promote cancer pain via fibroblasts (Aim 1) and determining the mechanisms underlying pain-associated sensory neuron activity-mediated tumor progression in a neuronal subtype-dependent manner (Aim 2). To achieve these aims, we have assembled a multi-disciplinary team consisting of cancer neuroscientists (Yuan Pan, PhD and Xiaofan Guo, MD-PhD), pain researchers (Peter Grace, PhD and Andrew Shepherd, PhD), an MPNST physician-scientist (Angela Hirbe, MD-PhD), a pathologist (John Chrisinger, MD), a bioinformatician (Rajasekaran Mahalingam, PhD), biostatisticians (Chongliang Luo, PhD and Roland Bassett, PhD), and a data management and sharing expert (Robert Allaway, PhD). Together, we will leverage genetically engineered mice, mouse and human MPNST cells, human MPNST tumor specimens, and neuroscience approaches to test the hypothesis. Successful completion of these studies will uncover the mechanisms under which cancer pain-associated neuronal activity interacts with MPNST cells to drive malignancy. Findings from this study will open a new avenue for predicting prognosis and improving the survivorship and quality of life of patients with these deadly tumors.
