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PAP/REG3A favors perineural invasion in pancreatic adenocarcinoma and serves as a prognostic marker

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Abstract

Pancreatic ductal adenocarcinoma (PDA) is a fatal and insidious malignant disease for which clinicians’ tools are restricted by the current limits in knowledge of how tumor and stromal cells act during the disease. Among PDA hallmarks, neural remodeling (NR) and perineural invasion (PNI) drastically influence quality of life and patient survival. Indeed, NR and PNI are associated with neuropathic pain and metastasis, respectively, both of which impact clinicians’ decisions and therapeutic options. The aim of this study was to determine the impact and clinical relevance of the peritumoral microenvironment, through pancreatitis-associated protein (PAP/REG3A) expression, on PNI in pancreatic cancer. First, we demonstrated that, in PDA, PAP/REG3A is produced by inflamed acinar cells from the peritumoral microenvironment and then enhances the migratory and invasive abilities of cancer cells. More specifically, using perineural ex vivo assays we revealed that PAP/REG3A favors PNI through activation of the JAK/STAT signaling pathway in cancer cells. Finally, we analyzed the level of PAP/REG3A in blood from healthy donors or patients with PDA from three independent cohorts. Patients with high levels of PAP/REG3A had overall shorter survival as well as poor surgical outcomes with reduced disease-free survival. Our study provides a rationale for using the PAP/REG3A level as a biomarker to improve pancreatic cancer prognosis. It also suggests that therapeutic targeting of PAP/REG3A activity in PDA could limit tumor cell aggressiveness and PNI.

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Acknowledgements

We would like to thank Bruno Olivier from INSERM U1068 (Marseille, France) for his technical assistance, Laurence Borge from the U1068 Cell Culture Platform (Marseille, France), and Karim Sari and Régis Vitestelle of the animal colony facility “PSEA” (Marseille, France). This project was supported by SIRIC PACA-OUEST (Grant INCa-DGOS-Inserm 6038), the French National Institute of Cancer (INCa, PLBIO13-134), the European Research Council under the European Union’s Seventh Framework Program (FP/2007–2013)/ERC Grant Agreement No. [282036], the Instituto de Salud Carlos III (for CIBEREHD support) and FIS Grant, PI13/01224 to EF-P and PI13/02192 to MG, co-funded by FEDER-European Union. J.N., C.B., and J.R. were supported by the European Research Council under the European Union’s Seventh Framework Program (FP/2007-2013)/ERC Grant Agreement no. [282036]. S.L. was supported by the “Programme Investissements Avenir” from Aix-Marseille University and J.R. by “Cancéropole PACA”.

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Authors and Affiliations

  1. CRCM, INSERM, U1068, 13009, Marseille, France

    Jérémy Nigri, Christian Bressy, Julie Roques, Sophie Lac, Juan Iovanna & Richard Tomasini

  2. Paoli-Calmettes Institute, 13009, Marseille, France

    Jérémy Nigri, Christian Bressy, Julie Roques, Sophie Lac, Juan Iovanna & Richard Tomasini

  3. Aix-Marseille University, UM 105, 13009, Marseille, France

    Jérémy Nigri, Christian Bressy, Julie Roques, Sophie Lac, Juan Iovanna & Richard Tomasini

  4. CNRS, UMR7258, 13009, Marseille, France

    Jérémy Nigri, Christian Bressy, Julie Roques, Sophie Lac, Juan Iovanna & Richard Tomasini

  5. Gastrointestinal and Pancreatic Oncology, Hospital Clinic of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), IDIBAPS, Barcelona, Catalonia, Spain

    Meritxell Gironella & Elena Vila-Navarro

  6. DYNABIO S.A.S, Luminy Biotech Entreprises, 13288, Marseille, France

    Caroline Bontemps & Coraline Kozaczyk

  7. Department of Pathology, INSERM U1149, Hospital Beaujon, F-92110, Clichy, France

    Jérôme Cros

  8. INSERM UMR-S1147, University Paris Descartes, Paris, France

    Daniel Pietrasz & Jean-Baptiste Bachet

  9. Department of Hepatobiliary and Digestive Surgery, Hospital Pitié Salpêtrière, Paris, France

    Daniel Pietrasz & Jean-Baptiste Bachet

  10. Gastrointestinal Cancer Unit, University Clinic of Bruxelles, Erasme Hospital, 1070, Brussels, Belgium

    Raphaël Maréchal & Jean-Luc Van Laethem

  11. Sorbonne University, UPMC University, Paris 06, France

    Jean-Baptiste Bachet

  12. Department of Hepatogastroentérology, Groupe Hospitalier Pitié Salpêtrière, Paris, France

    Jean-Baptiste Bachet

  13. Experimental Pathology Department, Instituto de Investigación Biomédicas de Barcelona (IIBB-CSIC), CIBEREHD, IDIBAPS, Barcelona, Catalonia, Spain

    Emma Folch-Puy

  14. 163 Avenue de Luminy, Parc scientifique de Luminy, Case 915, 13288, Marseille Cedex 9, France

    Richard Tomasini

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  1. Jérémy Nigri
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  2. Meritxell Gironella
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Nigri, J., Gironella, M., Bressy, C. et al. PAP/REG3A favors perineural invasion in pancreatic adenocarcinoma and serves as a prognostic marker. Cell. Mol. Life Sci. 74, 4231–4243 (2017). https://doi.org/10.1007/s00018-017-2579-9

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