title: 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 cross-talk as a potential novel target in PDAC treatment.Cancer Res; 77(8); 1868-79. ©2017 AACR.
authors.affiliation: David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.|Gastroenterology and Nutrition Service, Memorial Sloan Kettering Cancer Center, New York, New York.|Division of Gastroenterology and Hepatology, Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Smrita
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Division of Gastroenterology and Hepatology, Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Ya-Yuan
authors.initials: YY
authors.lastname: Fu
authors.affiliation: David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Adrien
authors.initials: A
authors.lastname: Grimont
authors.affiliation: Weill Cornell Medical College, New York, New York.
authors.forename: Maren
authors.initials: M
authors.lastname: Ketcham
authors.affiliation: David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Kelly
authors.initials: K
authors.lastname: Lafaro
authors.affiliation: David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Saglimbeni
authors.affiliation: David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.|Gastrointestinal Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Gokce
authors.initials: G
authors.lastname: Askan
authors.affiliation: Division of Surgical Oncology, Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Bailey
authors.affiliation: David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jerry P
authors.initials: JP
authors.lastname: Melchor
authors.affiliation: David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Min Geol
authors.initials: MG
authors.lastname: Joo
authors.affiliation: David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Olivera
authors.initials: O
authors.lastname: Grbovic-Huezo
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland.
authors.forename: In-Hong
authors.initials: IH
authors.lastname: Yang
authors.affiliation: Gastrointestinal Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Olca
authors.initials: O
authors.lastname: Basturk
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Baker
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
authors.forename: Young
authors.initials: Y
authors.lastname: Park
authors.affiliation: Gastroenterology and Nutrition Service, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Kurtz
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
authors.forename: David
authors.initials: D
authors.lastname: Tuveson
authors.affiliation: David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. leachs@mskcc.org ppasric1@jhmi.edu.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Leach
authors.affiliation: Division of Gastroenterology and Hepatology, Johns Hopkins Hospital, Baltimore, Maryland. leachs@mskcc.org ppasric1@jhmi.edu.
authors.forename: Pankaj J
authors.initials: PJ
authors.lastname: Pasricha
mesh_terms: D016475:3T3 Cells; D000818:Animals; D063646:Carcinogenesis; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D055099:Neuroendocrine Cells / Q000378:metabolism / Q000473:pathology*; D010179:Pancreas / Q000294:innervation* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011230:Precancerous Conditions / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism / Q000473:pathology*; D013373:Substance P / Q000096:biosynthesis
chemical_list: D050796:STAT3 Transcription Factor; D013373:Substance P