Please use this identifier to cite or link to this item:
10.1172/JCI166333
Title: | Phenotype screens of murine pancreatic cancer identify a Tgf-α-Ccl2-paxillin axis driving human-like neural invasion |
Authors: | Wang, Xiaobo Istvanffy, Rouzanna Ye, Linhan Teller, Steffen Laschinger, Melanie Diakopoulos, Kalliope N. Görgülü, Kıvanç Li, Qiaolin Ren, Lei Jäger, Carsten Steiger, Katja Muckenhuber, Alexander Vilne, Baiba Çifcibaşı, Kaan Reyes, Carmen Mota Yurteri, Ümmügülsüm Kießler, Maximilian Gürçınar, Ibrahim Halil Sugden, Maya Yıldızhan, Saliha Elif Sezerman, Osman Uğur Çilingir, Sümeyye Süyen, Güldal Reichert, Maximilian Schmid, Roland M. Bärthel, Stefanie Oellinger, Rupert Krüger, Achim Rad, Roland Saur, Dieter Algül, Hana Friess, Helmut Lesina, Marina Ceyhan, Güralp Onur Demir, Ihsan Ekin Bioinformatics Group |
Keywords: | Humans;Animals;Mice;Transforming Growth Factor alpha/genetics;Paxillin/genetics;Pancreatic Neoplasms/pathology;Carcinoma, Pancreatic Ductal/metabolism;Phenotype;Cell Line, Tumor;Pancreatic Neoplasms;3.1 Basic medicine;3.2 Clinical medicine;1.1. Scientific article indexed in Web of Science and/or Scopus database;General Medicine;SDG 3 - Good Health and Well-being |
Issue Date: | Jan-2023 |
Citation: | Wang , 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 |
Abstract: | 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. |
Description: | Publisher Copyright: Copyright: © 2023, Wang et al. |
DOI: | 10.1172/JCI166333 |
ISSN: | 0021-9738 |
Appears in Collections: | Research outputs from Pure / Zinātniskās darbības rezultāti no ZDIS Pure |
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