title: Stromal SLIT2 impacts on pancreatic cancer-associated neural remodeling.
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.
authors.affiliation: 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.
authors.forename: V
authors.initials: V
authors.lastname: Secq
authors.affiliation: CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France.
authors.forename: J
authors.initials: J
authors.lastname: Leca
authors.affiliation: CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France.
authors.forename: C
authors.initials: C
authors.lastname: Bressy
authors.affiliation: CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France.
authors.forename: F
authors.initials: F
authors.lastname: Guillaumond
authors.affiliation: CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France.
authors.forename: P
authors.initials: P
authors.lastname: Skrobuk
authors.affiliation: CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France.
authors.forename: J
authors.initials: J
authors.lastname: Nigri
authors.affiliation: CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France.
authors.forename: S
authors.initials: S
authors.lastname: Lac
authors.affiliation: 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.
authors.forename: M-N
authors.initials: MN
authors.lastname: Lavaut
authors.affiliation: CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France.
authors.forename: T-T
authors.initials: TT
authors.lastname: Bui
authors.affiliation: CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France.
authors.forename: A K
authors.initials: AK
authors.lastname: Thakur
authors.affiliation: Neuronexperts, Medical North Faculty, Marseille, France.
authors.forename: N
authors.initials: N
authors.lastname: Callizot
authors.affiliation: Neuronexperts, Medical North Faculty, Marseille, France.
authors.forename: R
authors.initials: R
authors.lastname: Steinschneider
authors.affiliation: CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France.
authors.forename: P
authors.initials: P
authors.lastname: Berthezene
authors.affiliation: CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France.
authors.forename: N
authors.initials: N
authors.lastname: Dusetti
authors.affiliation: Aix-Marseille University, INSERM, CRO2, UMR 911, Marseille 13385, France.
authors.forename: M
authors.initials: M
authors.lastname: Ouaissi
authors.affiliation: CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France.
authors.forename: V
authors.initials: V
authors.lastname: Moutardier
authors.affiliation: Molecular Endocrinology and Oncology Research Center, CHUL Research Center, Quebec City, QCue, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Calvo
authors.affiliation: INSERM UMR 1037, CRCT, University Toulouse III, Toulouse, France.
authors.forename: C
authors.initials: C
authors.lastname: Bousquet
authors.affiliation: 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.
authors.forename: S
authors.initials: S
authors.lastname: Garcia
authors.affiliation: CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France.
authors.forename: G
authors.initials: G
authors.lastname: Bidaut
authors.affiliation: CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France.
authors.forename: S
authors.initials: S
authors.lastname: Vasseur
authors.affiliation: CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France.
authors.forename: J L
authors.initials: JL
authors.lastname: Iovanna
authors.affiliation: CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France.
authors.forename: R
authors.initials: R
authors.lastname: Tomasini
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects; D002451:Cell Compartmentation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003470:Culture Media / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008819:Mice, Nude; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D059467:Transcriptome / Q000235:genetics; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism; D000098552:Slit Homolog 2 Protein
chemical_list: D015820:Cadherins; D003470:Culture Media; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D051176:beta Catenin; D000098552:Slit Homolog 2 Protein