Wang, XiaoboIstvanffy, RouzannaYe, LinhanTeller, SteffenLaschinger, MelanieDiakopoulos, Kalliope N.Görgülü, KıvançLi, QiaolinRen, LeiJäger, CarstenSteiger, KatjaMuckenhuber, AlexanderVilne, BaibaÇifcibaşı, KaanReyes, Carmen MotaYurteri, ÜmmügülsümKießler, MaximilianGürçınar, Ibrahim HalilSugden, MayaYıldızhan, Saliha ElifSezerman, Osman UğurÇilingir, SümeyyeSüyen, GüldalReichert, MaximilianSchmid, Roland M.Bärthel, StefanieOellinger, RupertKrüger, AchimRad, RolandSaur, DieterAlgül, HanaFriess, HelmutLesina, MarinaCeyhan, Güralp OnurDemir, Ihsan Ekin2023-12-042023-12-042023-01Wang, 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/JCI1663330021-9738Mendeley: 4ea849d2-2bd0-3eb9-82b4-b781e6ec0495https://dspace.rsu.lv/jspui/handle/123456789/15025Publisher Copyright: Copyright: © 2023, Wang et al.Solid 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.7467444enginfo:eu-repo/semantics/openAccessHumansAnimalsMiceTransforming Growth Factor alpha/geneticsPaxillin/geneticsPancreatic Neoplasms/pathologyCarcinoma, Pancreatic Ductal/metabolismPhenotypeCell Line, TumorPancreatic Neoplasms3.1 Basic medicine3.2 Clinical medicine1.1. Scientific article indexed in Web of Science and/or Scopus databaseGeneral MedicineSDG 3 - Good Health and Well-being/dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article10.1172/JCI166333http://www.scopus.com/inward/record.url?scp=85175742333&partnerID=8YFLogxKhttps://www.mendeley.com/catalogue/4ea849d2-2bd0-3eb9-82b4-b781e6ec0495/