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Stromal SLIT2 impacts on pancreatic cancer-associated neural remodeling.

Authors
  • Secq, V1
  • Leca, J2
  • Bressy, C2
  • Guillaumond, F2
  • Skrobuk, P2
  • Nigri, J2
  • Lac, S2
  • Lavaut, M-N1
  • Bui, T-T2
  • Thakur, A K2
  • Callizot, N3
  • Steinschneider, R3
  • Berthezene, P2
  • Dusetti, N2
  • Ouaissi, M4
  • Moutardier, V2
  • Calvo, E5
  • Bousquet, C6
  • Garcia, S1
  • Bidaut, G2
  • And 3 more
  • 1 1] CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France [2] Department of Pathology, Hospital North/Mediterranean University, Marseille, France. , (France)
  • 2 CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France. , (France)
  • 3 Neuronexperts, Medical North Faculty, Marseille, France. , (France)
  • 4 Aix-Marseille University, INSERM, CRO2, UMR 911, Marseille 13385, France. , (France)
  • 5 Molecular Endocrinology and Oncology Research Center, CHUL Research Center, Quebec City, QCue, Canada. , (Canada)
  • 6 INSERM UMR 1037, CRCT, University Toulouse III, Toulouse, France. , (France)
Type
Published Article
Journal
Cell Death and Disease
Publisher
Springer Nature
Publication Date
Jan 15, 2015
Volume
6
Identifiers
DOI: 10.1038/cddis.2014.557
PMID: 25590802
Source
Medline
License
Unknown

Abstract

Pancreatic ductal adenocarcinoma (PDA) is a critical health issue in the field of cancer, with few therapeutic options. Evidence supports an implication of the intratumoral microenvironment (stroma) on PDA progression. However, its contribution to the role of neuroplastic changes within the pathophysiology and clinical course of PDA, through tumor recurrence and neuropathic pain, remains unknown, neglecting a putative, therapeutic window. Here, we report that the intratumoral microenvironment is a mediator of PDA-associated neural remodeling (PANR), and we highlight factors such as 'SLIT2' (an axon guidance molecule), which is expressed by cancer-associated fibroblasts (CAFs), that impact on neuroplastic changes in human PDA. We showed that 'CAF-secreted SLIT2' increases neurite outgrowth from dorsal root ganglia neurons as well as from Schwann cell migration/proliferation by modulating N-cadherin/β-catenin signaling. Importantly, SLIT2/ROBO signaling inhibition disrupts this stromal/neural connection. Finally, we revealed that SLIT2 expression and CAFs are correlated with neural remodeling within human and mouse PDA. All together, our data demonstrate the implication of CAFs, through the secretion of axon guidance molecule, in PANR. Furthermore, it provides rationale to investigate the disruption of the stromal/neural compartment connection with SLIT2/ROBO inhibitors for the treatment of pancreatic cancer recurrence and pain.

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