Phenotype screens of murine pancreatic cancer identify a Tgf-α-Ccl2-paxillin axis driving human-like neural invasion

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dc.contributor.authorWang, Xiaobo
dc.contributor.authorIstvanffy, Rouzanna
dc.contributor.authorYe, Linhan
dc.contributor.authorTeller, Steffen
dc.contributor.authorLaschinger, Melanie
dc.contributor.authorDiakopoulos, Kalliope N.
dc.contributor.authorGörgülü, Kıvanç
dc.contributor.authorLi, Qiaolin
dc.contributor.authorRen, Lei
dc.contributor.authorJäger, Carsten
dc.contributor.authorSteiger, Katja
dc.contributor.authorMuckenhuber, Alexander
dc.contributor.authorVilne, Baiba
dc.contributor.authorÇifcibaşı, Kaan
dc.contributor.authorReyes, Carmen Mota
dc.contributor.authorYurteri, Ümmügülsüm
dc.contributor.authorKießler, Maximilian
dc.contributor.authorGürçınar, Ibrahim Halil
dc.contributor.authorSugden, Maya
dc.contributor.authorYıldızhan, Saliha Elif
dc.contributor.authorSezerman, Osman Uğur
dc.contributor.authorÇilingir, Sümeyye
dc.contributor.authorSüyen, Güldal
dc.contributor.authorReichert, Maximilian
dc.contributor.authorSchmid, Roland M.
dc.contributor.authorBärthel, Stefanie
dc.contributor.authorOellinger, Rupert
dc.contributor.authorKrüger, Achim
dc.contributor.authorRad, Roland
dc.contributor.authorSaur, Dieter
dc.contributor.authorAlgül, Hana
dc.contributor.authorFriess, Helmut
dc.contributor.authorLesina, Marina
dc.contributor.authorCeyhan, Güralp Onur
dc.contributor.authorDemir, Ihsan Ekin
dc.contributor.institutionBioinformatics Group
dc.date.accessioned2023-12-04T14:05:01Z
dc.date.available2023-12-04T14:05:01Z
dc.date.issued2023-01
dc.descriptionPublisher Copyright: Copyright: © 2023, Wang et al.
dc.description.abstractSolid cancers like pancreatic ductal adenocarcinoma (PDAC), a type of pancreatic cancer, frequently exploit nerves for rapid dissemination. This neural invasion (NI) is an independent prognostic factor in PDAC, but insufficiently modeled in genetically engineered mouse models (GEMM) of PDAC. Here, we systematically screened for human-like NI in Europe’s largest repository of GEMM of PDAC, comprising 295 different genotypes. This phenotype screen uncovered 2 GEMMs of PDAC with human-like NI, which are both characterized by pancreas-specific overexpression of transforming growth factor α (TGF-α) and conditional depletion of p53. Mechanistically, cancer-cell-derived TGF-α upregulated CCL2 secretion from sensory neurons, which induced hyperphosphorylation of the cytoskeletal protein paxillin via CCR4 on cancer cells. This activated the cancer migration machinery and filopodia formation toward neurons. Disrupting CCR4 or paxillin activity limited NI and dampened tumor size and tumor innervation. In human PDAC, phospho-paxillin and TGF-α–expression constituted strong prognostic factors. Therefore, we believe that the TGF-α-CCL2-CCR4-p-paxillin axis is a clinically actionable target for constraining NI and tumor progression in PDAC.en
dc.description.statusPeer reviewed
dc.format.extent7467444
dc.identifier.citationWang, X, Istvanffy, R, Ye, L, Teller, S, Laschinger, M, Diakopoulos, K N, Görgülü, K, Li, Q, Ren, L, Jäger, C, Steiger, K, Muckenhuber, A, Vilne, B, Çifcibaşı, K, Reyes, C M, Yurteri, Ü, Kießler, M, Gürçınar, I H, Sugden, M, Yıldızhan, S E, Sezerman, O U, Çilingir, S, Süyen, G, Reichert, M, Schmid, R M, Bärthel, S, Oellinger, R, Krüger, A, Rad, R, Saur, D, Algül, H, Friess, H, Lesina, M, Ceyhan, G O & Demir, I E 2023, 'Phenotype screens of murine pancreatic cancer identify a Tgf-α-Ccl2-paxillin axis driving human-like neural invasion', Journal of Clinical Investigation, vol. 133, no. 21, e166333. https://doi.org/10.1172/JCI166333
dc.identifier.doi10.1172/JCI166333
dc.identifier.issn0021-9738
dc.identifier.otherMendeley: 4ea849d2-2bd0-3eb9-82b4-b781e6ec0495
dc.identifier.urihttps://dspace.rsu.lv/jspui/handle/123456789/15025
dc.identifier.urlhttp://www.scopus.com/inward/record.url?scp=85175742333&partnerID=8YFLogxK
dc.identifier.urlhttps://www.mendeley.com/catalogue/4ea849d2-2bd0-3eb9-82b4-b781e6ec0495/
dc.language.isoeng
dc.relation.ispartofJournal of Clinical Investigation
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectHumans
dc.subjectAnimals
dc.subjectMice
dc.subjectTransforming Growth Factor alpha/genetics
dc.subjectPaxillin/genetics
dc.subjectPancreatic Neoplasms/pathology
dc.subjectCarcinoma, Pancreatic Ductal/metabolism
dc.subjectPhenotype
dc.subjectCell Line, Tumor
dc.subjectPancreatic Neoplasms
dc.subject3.1 Basic medicine
dc.subject3.2 Clinical medicine
dc.subject1.1. Scientific article indexed in Web of Science and/or Scopus database
dc.subjectGeneral Medicine
dc.subjectSDG 3 - Good Health and Well-being
dc.titlePhenotype screens of murine pancreatic cancer identify a Tgf-α-Ccl2-paxillin axis driving human-like neural invasionen
dc.type/dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article

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