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.

β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer

“…While gastric cancer is clearly stimulated by cholinergic signaling, recent studies in mice showed that in PanINs, sensory innervation increased dramatically, contributing to invasive tumor spread (Stopczynski et al, 2014), which can be inhibited by ablation of sensory neurons (Saloman et al, 2016). Sensory nerves may contribute to PDAC progression in part through direct signaling to neoplastic neuroendocrine cells expressing the substance P (SP) receptor Neurokinin 1-R (NK1-R) (Sinha et al, 2017). Nevertheless, our current study demonstrates that stress-dependent sympathetic signaling can induce PDAC in preneoplastic lesions (i.e.…”

Ameloblastomas Exhibit Stem Cell Potential, Possess Neurotrophic Properties, and Establish Connections with Trigeminal Neurons

“…We also showed that ameloblastoma malignant cells themselves exert strong neurotrophic effects. Nerve-derived signals could therefore be fundamental for ameloblastoma pathogenesis, as already proven for other cancers [21,23,26,27,77,78]. Innervation might indeed directly modulate ameloblastoma proliferation and invasiveness.…”

“…Only recently a few studies have started shedding light on the fundamental role of innervation for cancer onset and progression. It was indeed shown that nerve-derived signals promote the progression of different types of tumor, including gastric, pancreatic, breast, and oral cancers [20,21,23,25,26,29,75]. For instance, in prostate cancer, recruitment of nerve fibers to cancer tissue increases tumor proliferation and is associated with a higher risk of recurrence and metastasis [21].…”

“…In the last few decades, increasing evidence indicates that innervation plays an active role in cancer onset, progression, and metastatization [20][21][22][23][24][25][26][27]. Many classes of cancer are infiltrated by nerve fibers, and their presence is associated with poor prognosis [21][22][23].…”

“…Indeed, experiments conducted on mice have shown that denervation of primary tumors results in a strong decrease in tumor growth and dissemination. These observations were first conducted on prostate cancers [25], but in recent years nerve dependence has been demonstrated for many classes of tumors, including gastric cancers [27], melanomas [20], pancreatic cancers [24,26], and head and neck squamous cell carcinomas [22,23]. In addition to driving cancer progression, nerve fibers are the mediators of cancer-associated pain [28,29].…”