PanIN Neuroendocrine Cells Promote Tumorigenesis via Neuronal Cross-talk

Abstract

Nerves are a notable feature of the tumor microenvironment in some epithelial tumors, but their role in the malignant progression of pancreatic ductal adenocarcinoma (PDAC) is uncertain. Here we identify dense innervation in the microenvironment of precancerous pancreatic lesions, known as pancreatic intraepithelial neoplasms (PanIN), and describe a unique subpopulation of neuroendocrine PanIN cells that express the neuropeptide substance P (SP) receptor Neurokinin 1-R (NK1-R). Using organoid culture, we demonstrated that sensory neurons promoted the proliferation of PanIN organoids via SP-NK1-R signaling and Stat3 activation. Nerve-responsive neuroendocrine cells exerted trophic influences and potentiated global PanIN organoid growth. Sensory denervation of a genetically engineered mouse model of PDAC led to loss of Stat3 activation, a decrease in the neoplastic neuroendocrine cell population, and impaired PanIN progression to tumor. Overall, our data provide evidence that nerves of the PanIN microenvironment promote oncogenesis, likely via direct signaling to neoplastic neuroendocrine cells capable of trophic influences. These findings identify neuroepithelial crosstalk as a potential novel target in PDAC treatment.

Tumor Neurobiology and the War of Nerves in Cancer

“…This observation argues for a distinct suppressive effect by the vagal cholinergic axons. It is important to note that whereas autonomic nerves are implicated in prostate ( 5 ) and gastric ( 8 ) cancers, sensory nerves are also involved in the stimulation of pancreatic cancer progression ( 9,13,14 ). Interestingly, a dense substance P-positive sensory innervation has been described in precancerous pancreatic lesions, and neuroendocrine cells were found to express the substance P receptor neurokinin 1-R (NK1R), suggesting neuroendocrine cells as the mediators of sensory nerve stimulation in early pancreatic tumorigenesis ( 14 ).…”

“…It is important to note that whereas autonomic nerves are implicated in prostate ( 5 ) and gastric ( 8 ) cancers, sensory nerves are also involved in the stimulation of pancreatic cancer progression ( 9,13,14 ). Interestingly, a dense substance P-positive sensory innervation has been described in precancerous pancreatic lesions, and neuroendocrine cells were found to express the substance P receptor neurokinin 1-R (NK1R), suggesting neuroendocrine cells as the mediators of sensory nerve stimulation in early pancreatic tumorigenesis ( 14 ). The stimulatory role of sensory nerves has also been found in basal cell carcinomas, a nonmelanoma form of skin cancer emerging from epithelial cells, where surgical ablation of sensory cutaneous nerves in hair follicles blunts tumor formation via a mechanism involving the activation of nerve-derived hedgehog signaling in epithelial cells (15).…”

“…2). On the one hand, sensory (9,14) and sympathetic (10) nerves stimulate the growth of pancreatic cancer cells, through neurokinin receptor and adrenergic signaling, respectively, whereas on the other hand parasympathetic nerves suppress cancer stemness through cholinergic signaling (11). It is well known that a yin-yang type of regulation by sympathetic versus parasympathetic nerves regulates cardiac function (55), and whether the principle of opposing neural effect also applies to the regulation of cancer progression warrants further exploration.…”

Sympathetic axonal sprouting induces changes in macrophage populations and protects against pancreatic cancer

“…As the late denervation experiments were performed by surgical resection of nerves around the celiac-superior mesenteric ganglion complex 8 , the observed effects may more probably result from elimination of the sensory component of these mixed sympathetic-sensory nerves. Indeed, previous studies reported that selective depletion or inactivation of sensory nerve fibers reduced tumor growth and prolongated overall survival in KPC mice 38,39 .…”

Cancer exosomes induce tumor neo-neurogenesis potentiating tumor growth

“…For instance, in prostate cancer, recruitment of nerve fibers to cancer tissue is associated with higher tumor proliferative indices and a higher risk of recurrence and metastasis (5). Denervation studies in pre-clinical and genetically engineered mouse cancer models support a functional contribution of neural elements in disease progression (8,9) (10). These studies strongly indicate that the nervous system is not a bystander but instead an active participant in carcinogenesis and cancer progression.…”