Phenotype screens of murine pancreatic cancer identify a Tgf-α-Ccl2-paxillin axis driving human-like neural invasion
Xiaobo Wang, … , Güralp Onur Ceyhan, Ihsan Ekin Demir
Xiaobo Wang, … , Güralp Onur Ceyhan, Ihsan Ekin Demir
Published August 22, 2023
Citation Information: J Clin Invest. 2023;133(21):e166333. https://doi.org/10.1172/JCI166333.
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Research Article Oncology

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

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.

Authors

Xiaobo Wang, Rouzanna Istvanffy, Linhan Ye, Steffen Teller, Melanie Laschinger, Kalliope N. Diakopoulos, Kıvanç Görgülü, Qiaolin Li, Lei Ren, Carsten Jäger, Katja Steiger, Alexander Muckenhuber, Baiba Vilne, Kaan Çifcibaşı, Carmen Mota Reyes, Ümmügülsüm Yurteri, Maximilian Kießler, Ibrahim Halil Gürçınar, Maya Sugden, Saliha Elif Yıldızhan, Osman Uğur Sezerman, Sümeyye Çilingir, Güldal Süyen, Maximilian Reichert, Roland M. Schmid, Stefanie Bärthel, Rupert Oellinger, Achim Krüger, Roland Rad, Dieter Saur, Hana Algül, Helmut Friess, Marina Lesina, Güralp Onur Ceyhan, Ihsan Ekin Demir

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Figure 4

Paxillin phosphorylation in cancer cells is associated with poorer survival in patients with PDAC.

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Paxillin phosphorylation in cancer cells is associated with poorer survi...
(A) Representative images of consecutive sections from human PDAC resection specimens stained for p-paxillin (brown), the neural marker PGP9.5 (pink), cancer cell marker pan-CK (brown) and counterstained with haematoxylin. (B) Graphs showing the percentage of p-paxillin content in cancer cells located distal and proximal to nerves. (C) Representative images of consecutive sections from patient-derived PDAC samples stained with paxillin and p-paxillin (brown) and counterstained with hematoxylin. (D) Graphs indicating relative content of p-paxillin to paxillin in low-p-paxillin and high p-paxillin groups of patients with PDAC. (E) Kaplan-Meier curves showing percentage survival of patients with low p-paxillin content (black line) and high p-paxillin content (red line). The cut-off value for p-paxillin content was set at 4% stained cells in all analyzed areas. (F) Graphs showing the percentage of CCL2 content in low-p-paxillin and high p-paxillin groups of patients with PDAC. (G) Graphs showing the percentage of lymph nodes infiltrated with tumor cells to all lymph nodes analyzed in low-p-paxillin and high p-paxillin groups of patients with PDAC. Scale bars: 20 μm. All results in graphs are shown as a mean value ± SEM. For the statistical analyses we used Mann-Whitney test (B, D, and F), and the Mantel-Cox test (E). The P value ˂ 0.05 was considered to have significance.