PanIN neuroendocrine cells promote tumorigenesis via neuronal cross-talk

Smrita Sinha, Ya Yuan Fu, Adrien Grimont, Maren Ketcham, Kelly Lafaro, Joseph A. Saglimbeni, Gokce Askan, Jennifer M. Bailey, Jerry P. Melchor, Yi Zhong, Min Geol Joo, Olivera Grbovic-Huezo, In Hong Yang, Olca Basturk, Lindsey Baker, Young Park, Robert C. Kurtz, David Tuveson, Steven D. Leach, Pankaj J. Pasricha

Research output: Contribution to journalArticle

Abstract

Nerves are a notable feature of the tumormicroenvironment 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. Nerveresponsive 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.

Original languageEnglish (US)
Pages (from-to)1868-1879
Number of pages12
JournalCancer Research
Volume77
Issue number8
DOIs
StatePublished - Apr 15 2017

Fingerprint

Neuroendocrine Cells
Carcinoma in Situ
Pancreatic Neoplasms
Carcinogenesis
Organoids
Adenocarcinoma
Neurokinin-1 Receptors
Denervation
Sensory Receptor Cells
Substance P
Neuropeptides
Neoplasms
Growth
Population

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

PanIN neuroendocrine cells promote tumorigenesis via neuronal cross-talk. / Sinha, Smrita; Fu, Ya Yuan; Grimont, Adrien; Ketcham, Maren; Lafaro, Kelly; Saglimbeni, Joseph A.; Askan, Gokce; Bailey, Jennifer M.; Melchor, Jerry P.; Zhong, Yi; Joo, Min Geol; Grbovic-Huezo, Olivera; Yang, In Hong; Basturk, Olca; Baker, Lindsey; Park, Young; Kurtz, Robert C.; Tuveson, David; Leach, Steven D.; Pasricha, Pankaj J.

In: Cancer Research, Vol. 77, No. 8, 15.04.2017, p. 1868-1879.

Research output: Contribution to journalArticle

Sinha, S, Fu, YY, Grimont, A, Ketcham, M, Lafaro, K, Saglimbeni, JA, Askan, G, Bailey, JM, Melchor, JP, Zhong, Y, Joo, MG, Grbovic-Huezo, O, Yang, IH, Basturk, O, Baker, L, Park, Y, Kurtz, RC, Tuveson, D, Leach, SD & Pasricha, PJ 2017, 'PanIN neuroendocrine cells promote tumorigenesis via neuronal cross-talk', Cancer Research, vol. 77, no. 8, pp. 1868-1879. https://doi.org/10.1158/0008-5472.CAN-16-0899-T
Sinha, Smrita ; Fu, Ya Yuan ; Grimont, Adrien ; Ketcham, Maren ; Lafaro, Kelly ; Saglimbeni, Joseph A. ; Askan, Gokce ; Bailey, Jennifer M. ; Melchor, Jerry P. ; Zhong, Yi ; Joo, Min Geol ; Grbovic-Huezo, Olivera ; Yang, In Hong ; Basturk, Olca ; Baker, Lindsey ; Park, Young ; Kurtz, Robert C. ; Tuveson, David ; Leach, Steven D. ; Pasricha, Pankaj J. / PanIN neuroendocrine cells promote tumorigenesis via neuronal cross-talk. In: Cancer Research. 2017 ; Vol. 77, No. 8. pp. 1868-1879.
@article{4029ea109a4240e8aed3275183a0ff7a,
title = "PanIN neuroendocrine cells promote tumorigenesis via neuronal cross-talk",
abstract = "Nerves are a notable feature of the tumormicroenvironment 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. Nerveresponsive 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.",
author = "Smrita Sinha and Fu, {Ya Yuan} and Adrien Grimont and Maren Ketcham and Kelly Lafaro and Saglimbeni, {Joseph A.} and Gokce Askan and Bailey, {Jennifer M.} and Melchor, {Jerry P.} and Yi Zhong and Joo, {Min Geol} and Olivera Grbovic-Huezo and Yang, {In Hong} and Olca Basturk and Lindsey Baker and Young Park and Kurtz, {Robert C.} and David Tuveson and Leach, {Steven D.} and Pasricha, {Pankaj J.}",
year = "2017",
month = "4",
day = "15",
doi = "10.1158/0008-5472.CAN-16-0899-T",
language = "English (US)",
volume = "77",
pages = "1868--1879",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "8",

}

TY - JOUR

T1 - PanIN neuroendocrine cells promote tumorigenesis via neuronal cross-talk

AU - Sinha, Smrita

AU - Fu, Ya Yuan

AU - Grimont, Adrien

AU - Ketcham, Maren

AU - Lafaro, Kelly

AU - Saglimbeni, Joseph A.

AU - Askan, Gokce

AU - Bailey, Jennifer M.

AU - Melchor, Jerry P.

AU - Zhong, Yi

AU - Joo, Min Geol

AU - Grbovic-Huezo, Olivera

AU - Yang, In Hong

AU - Basturk, Olca

AU - Baker, Lindsey

AU - Park, Young

AU - Kurtz, Robert C.

AU - Tuveson, David

AU - Leach, Steven D.

AU - Pasricha, Pankaj J.

PY - 2017/4/15

Y1 - 2017/4/15

N2 - Nerves are a notable feature of the tumormicroenvironment 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. Nerveresponsive 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.

AB - Nerves are a notable feature of the tumormicroenvironment 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. Nerveresponsive 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.

UR - http://www.scopus.com/inward/record.url?scp=85018803901&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85018803901&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-16-0899-T

DO - 10.1158/0008-5472.CAN-16-0899-T

M3 - Article

C2 - 28386018

AN - SCOPUS:85018803901

VL - 77

SP - 1868

EP - 1879

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 8

ER -