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dc.contributor.author | Djurec, Magdolna | |
dc.contributor.author | Graña Castro, Osvaldo | |
dc.contributor.author | Lee, Albert | |
dc.contributor.author | Troulé, Kevin | |
dc.contributor.author | Espinet, Elisa | |
dc.contributor.author | Cabras, Lavinia | |
dc.contributor.author | Navas, Carolina | |
dc.contributor.author | Blasco, María Teresa | |
dc.contributor.author | Martín-Díaz, Laura | |
dc.contributor.author | Burdiel, Miranda | |
dc.contributor.author | Li, Jing | |
dc.contributor.author | Liu, Zhaoqi | |
dc.contributor.author | Vallespinós, Mireia | |
dc.contributor.author | Sanchez-Bueno, Francisco | |
dc.contributor.author | Sprick, Martin R | |
dc.contributor.author | Trumpp, Andreas | |
dc.contributor.author | Sainz, Bruno | |
dc.contributor.author | Al-Shahrour, Fatima | |
dc.contributor.author | Rabadan, Raul | |
dc.contributor.author | Guerra, Carmen | |
dc.contributor.author | Barbacid, Mariano | |
dc.date.accessioned | 2019-08-20T06:04:16Z | |
dc.date.available | 2019-08-20T06:04:16Z | |
dc.date.issued | 2018-02-06 | |
dc.identifier.citation | Proc Natl Acad Sci U S A. 2018 ;115(6):E1147-E1156. | es_ES |
dc.identifier.issn | 0027-8424 | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/8305 | |
dc.description.abstract | Pancreatic ductal adenocarcinoma (PDAC) is characterized by the presence of abundant desmoplastic stroma primarily composed of cancer-associated fibroblasts (CAFs). It is generally accepted that CAFs stimulate tumor progression and might be implicated in drug resistance and immunosuppression. Here, we have compared the transcriptional profile of PDGFRα+ CAFs isolated from genetically engineered mouse PDAC tumors with that of normal pancreatic fibroblasts to identify genes potentially implicated in their protumorigenic properties. We report that the most differentially expressed gene, Saa3, a member of the serum amyloid A (SAA) apolipoprotein family, is a key mediator of the protumorigenic activity of PDGFRα+ CAFs. Whereas Saa3-competent CAFs stimulate the growth of tumor cells in an orthotopic model, Saa3-null CAFs inhibit tumor growth. Saa3 also plays a role in the cross talk between CAFs and tumor cells. Ablation of Saa3 in pancreatic tumor cells makes them insensitive to the inhibitory effect of Saa3-null CAFs. As a consequence, germline ablation of Saa3 does not prevent PDAC development in mice. The protumorigenic activity of Saa3 in CAFs is mediated by Mpp6, a member of the palmitoylated membrane protein subfamily of the peripheral membrane-associated guanylate kinases (MAGUK). Finally, we interrogated whether these observations could be translated to a human scenario. Indeed, SAA1, the ortholog of murine Saa3, is overexpressed in human CAFs. Moreover, high levels of SAA1 in the stromal component correlate with worse survival. These findings support the concept that selective inhibition of SAA1 in CAFs may provide potential therapeutic benefit to PDAC patients. | es_ES |
dc.description.sponsorship | We thank Beatriz Jiménez, María del Carmen G. Lechuga, Marta San Roman, Raquel Villar, and Silvia Jiménez for excellent technical assistance; Jaime Muñoz and Sagrario Ortega (CNIO Transgenic Unit) for help in generating Saa3-null mice; Isabel Aragón, Mayte Lamparero, Alejandra López, Patricia Villanueva, and Isabel Blanco (CNIO Animal Facility)for mouse work; Gloria Visdomine, Cristina Peñalba, and Francisca Mulero (CNIO Molecular Imaging Unit) for ultrasound studies; Manuel Pérez, Jesús Gómez, and Diego Megías (CNIO Confocal Microscopy Unit) for confocal im-aging; Ultan Cronin and LolaMartínez (Flow Cytometry Unit) for FACS analysis; Nuria Cabrera and Alba de Martino (Histopathology Unit) for histopatholog-ical analysis; Manuel Morente for his advice with immunohistochemical (CNIO Tumor Bank); Corinna Klein for advice concerning the orthotopic studies; and the German Cancer Research Center-Heidelberg Center for Personalized Oncology (DKFZ-HIPO) for technical support and funding through the Grant HIPO-015. This work was supported by European Research CouncilGrants ERC-AG/250297-RAS AHEAD and ERC-AG/695566-THERACAN, Spanish Ministry of Economy and Competiti veness Grant SAF2014-59864-R, andAsociación Española contra el Cáncer Grant GC16173694BARB (to M. Barbacid).M.D. was supported by a fellowship from La Caixa International Fellowship Program. M. Barbacid is the recipient of an Endowed Chair from the AXA Research Fund. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | National Academy of Sciences | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | * |
dc.subject | CAFs | es_ES |
dc.subject | PDAC | es_ES |
dc.subject | Saa3 | es_ES |
dc.subject | mouse models | es_ES |
dc.subject | stroma | es_ES |
dc.subject.mesh | Animals | es_ES |
dc.subject.mesh | Cancer-Associated Fibroblasts | es_ES |
dc.subject.mesh | Carcinoma, Pancreatic Ductal | es_ES |
dc.subject.mesh | Cell Movement | es_ES |
dc.subject.mesh | Cell Proliferation | es_ES |
dc.subject.mesh | Female | es_ES |
dc.subject.mesh | High-Throughput Nucleotide Sequencing | es_ES |
dc.subject.mesh | Humans | es_ES |
dc.subject.mesh | Mice | es_ES |
dc.subject.mesh | Mice, Inbred C57BL | es_ES |
dc.subject.mesh | Mice, Knockout | es_ES |
dc.subject.mesh | Pancreas | es_ES |
dc.subject.mesh | Pancreatic Neoplasms | es_ES |
dc.subject.mesh | Serum Amyloid A Protein | es_ES |
dc.subject.mesh | Stromal Cells | es_ES |
dc.subject.mesh | Tumor Microenvironment | es_ES |
dc.title | Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts in pancreatic tumors | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Atribución-NoComercial-CompartirIgual 4.0 Internacional | * |
dc.identifier.pubmedID | 29351990 | es_ES |
dc.format.volume | 115 | es_ES |
dc.format.number | 6 | es_ES |
dc.format.page | E1147-E1156 | es_ES |
dc.identifier.doi | 10.1073/pnas.1717802115 | es_ES |
dc.contributor.funder | German Cancer Research Center | |
dc.contributor.funder | Unión Europea. Comisión Europea. European Research Council (ERC) | |
dc.contributor.funder | Ministerio de Economía y Competitividad (España) | |
dc.contributor.funder | Asociación Española Contra el Cáncer | |
dc.contributor.funder | Fundación La Caixa | |
dc.contributor.funder | Fundación AXA | |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 1091-6490 | es_ES |
dc.relation.publisherversion | https://doi.org/10.1073/pnas.1717802115 | es_ES |
dc.identifier.journal | Proceedings of the National Academy of Sciences of the United States of America | es_ES |
dc.repisalud.institucion | CNIO | es_ES |
dc.repisalud.orgCNIO | CNIO::Grupos de investigación::Grupo de Oncología Experimental | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/EC/FP7/250297 | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/EC/FP7/695566 | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/SAF2014-59864-R | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/GC16173694BARB | es_ES |
dc.rights.accessRights | open access | es_ES |