TY - JOUR
T1 - Phenotype screens of murine pancreatic cancer identify a Tgf-α-Ccl2-paxillin axis driving human-like neural invasion
AU - Wang, Xiaobo
AU - Istvanffy, Rouzanna
AU - Ye, Linhan
AU - Teller, Steffen
AU - Laschinger, Melanie
AU - Diakopoulos, Kalliope N.
AU - Görgülü, Kıvanç
AU - Li, Qiaolin
AU - Ren, Lei
AU - Jäger, Carsten
AU - Steiger, Katja
AU - Muckenhuber, Alexander
AU - Vilne, Baiba
AU - Çifcibaşı, Kaan
AU - Reyes, Carmen Mota
AU - Yurteri, Ümmügülsüm
AU - Kießler, Maximilian
AU - Gürçınar, Ibrahim Halil
AU - Sugden, Maya
AU - Yıldızhan, Saliha Elif
AU - Sezerman, Osman Uğur
AU - Çilingir, Sümeyye
AU - Süyen, Güldal
AU - Reichert, Maximilian
AU - Schmid, Roland M.
AU - Bärthel, Stefanie
AU - Oellinger, Rupert
AU - Krüger, Achim
AU - Rad, Roland
AU - Saur, Dieter
AU - Algül, Hana
AU - Friess, Helmut
AU - Lesina, Marina
AU - Ceyhan, Güralp Onur
AU - Demir, Ihsan Ekin
N1 - Publisher Copyright:
Copyright: © 2023, Wang et al.
PY - 2023/1
Y1 - 2023/1
N2 - 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.
AB - 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.
KW - Humans
KW - Animals
KW - Mice
KW - Transforming Growth Factor alpha/genetics
KW - Paxillin/genetics
KW - Pancreatic Neoplasms/pathology
KW - Carcinoma, Pancreatic Ductal/metabolism
KW - Phenotype
KW - Cell Line, Tumor
KW - Pancreatic Neoplasms
UR - http://www.scopus.com/inward/record.url?scp=85175742333&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/4ea849d2-2bd0-3eb9-82b4-b781e6ec0495/
U2 - 10.1172/JCI166333
DO - 10.1172/JCI166333
M3 - Article
C2 - 37607005
AN - SCOPUS:85175742333
SN - 0021-9738
VL - 133
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 21
M1 - e166333
ER -