PanIN Neuroendocrine Cells Promote Tumorigenesis via Neuronal Cross-talk
| Autor: | Gokce Askan, Robert C. Kurtz, In Hong Yang, Yi Zhong, Olca Basturk, Olivera Grbovic-Huezo, Jerry P. Melchor, Min Geol Joo, Joseph Saglimbeni, Ya-Yuan Fu, Kelly J. Lafaro, Steven D. Leach, Jennifer M. Bailey, Pankaj J. Pasricha, Adrien Grimont, Maren Ketcham, David A. Tuveson, Lindsey A. Baker, Young-Kyu Park, Smrita Sinha |
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| Rok vydání: | 2017 |
| Předmět: |
STAT3 Transcription Factor
0301 basic medicine Cancer Research Pathology medicine.medical_specialty Sensory Receptor Cells endocrine system diseases Carcinogenesis Population Substance P Biology medicine.disease_cause Article Mice 03 medical and health sciences 0302 clinical medicine Neuroendocrine Cells Ganglia Spinal medicine Organoid Animals Humans education Pancreas Neuroendocrine cell Tumor microenvironment education.field_of_study HEK 293 cells 3T3 Cells Mice Inbred C57BL Pancreatic Neoplasms Neuroepithelial cell Disease Models Animal HEK293 Cells 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer research Precancerous Conditions Carcinoma Pancreatic Ductal |
| Zdroj: | Cancer Research. 77:1868-1879 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-16-0899-t |
| Popis: | 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 cross-talk as a potential novel target in PDAC treatment. Cancer Res; 77(8); 1868–79. ©2017 AACR. |
| Databáze: | OpenAIRE |
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