There is a growing body of evidence indicating that peripheral neuron signaling mechanisms contribute to the prognosis, response to therapy, and pain associated with complex disorders such as cancer and chronic inflammatory diseases. Cross-talk between the nervous and immune system is critical for the regulation of homeostasis as well as the body’s response to trauma or infection. Within this context, ongoing projects are focused on: 1) sensory neuron signaling during homeostasis and nerve injury 2) pancreatitis, 3) pancreatic cancer, 4) cancer or treatment related pain, and 5) neuro-immune mechanisms that contribute to pathogenesis. Many of the specific questions addressed in our lab are derived from clinical observations; the lab has ongoing collaborations with clinicians enabling comparative analysis of pre-clinical models and patients.
Pancreatitis is a debilitating disease characterized by a high incidence of abdominal pain. While it is classically considered an inflammatory disease, over one quarter of patients also exhibit signs and symptoms associated with nerve injury. Less than one third of patients achieve pain relief with currently available analgesics and pain-relieving interventions. Utilizing both classical animal models of pancreatitis as well as a novel optogenetic model of pancreas pain, we are investigating the signaling mechanisms that contribute to these specific sub-types of pain within the context of pancreatic disease. Direct activation of nociceptors using light enables us to isolate the role of sensory neurons in the absence of mechanical perturbations and injury. Our result suggest that neural activation alone is sufficient to induce 2 of the 3 diagnostic criteria for acute pancreatitis.
Human pancreas tumor exhibits close association between intratumoral nerve axons (red) and B and T lymphocytes, (green and yellow, respectively)
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Neuro-immune regulation of the tumor microenvironment
(Collaboration with Dr. Vignali, Department of Immunology and Tumor Microenvironment Program)
Clinically, several tumor types are associated with significant sprouting and hypertrophy of peripheral axons resulting in more innervation than that found in the normal healthy organ. Furthermore, the extent of pain and sensorimotor deficits is associated with penetration of the nerves by tumor and immune cells, a phenomenon called perineural invasion. This study involves investigating mechanisms associated with this neuroplasticity in animal models and human tumor tissues.
Given that the tumor microenvironment often has a significant immune infiltration characterized by a suppressive phenotype, we have expanded this line of investigation to understand how peripheral neurons regulate tumor immune profiles. Furthermore, recent studies have demonstrated that proteins considered to be immune modulators are expressed by sensory neurons. Current studies are designed to determine if neuronal expression of immune proteins directly contributes to the neuronal regulation of tumor growth.