Z Gastroenterol 2021; 59(08): e191
DOI: 10.1055/s-0041-1733568
Pankreas Karzinogenese II
Montag, 13. September 2021, 13:30-14:50 Uhr, After-Work-Stream: Kanal 1
Pankreas

Neuron-triggered CCL2/CCR4/p-Paxilin pathway as a novel mechanism of neural invasion in pancreatic adenocarcinoma

R Istvánffy
1   Klinik und Poliklinik für Chirurgie, Klinikum r.d. Isar, TUM, München, Deutschland
,
X Wang
1   Klinik und Poliklinik für Chirurgie, Klinikum r.d. Isar, TUM, München, Deutschland
,
S Teller
1   Klinik und Poliklinik für Chirurgie, Klinikum r.d. Isar, TUM, München, Deutschland
,
M Laschinger
1   Klinik und Poliklinik für Chirurgie, Klinikum r.d. Isar, TUM, München, Deutschland
,
K Diakopoulos
2   Klinikum r.d. Isar, TUM, Department of Internal Medicine II & Comprehensive Cancer Center Munich, München, Deutschland
,
K Görgülu
2   Klinikum r.d. Isar, TUM, Department of Internal Medicine II & Comprehensive Cancer Center Munich, München, Deutschland
,
H Algül
2   Klinikum r.d. Isar, TUM, Department of Internal Medicine II & Comprehensive Cancer Center Munich, München, Deutschland
,
H Friess
1   Klinik und Poliklinik für Chirurgie, Klinikum r.d. Isar, TUM, München, Deutschland
,
M Lesina
2   Klinikum r.d. Isar, TUM, Department of Internal Medicine II & Comprehensive Cancer Center Munich, München, Deutschland
,
Ceyhan GO
3   Acibadem Mehmet Ali Aydinlar University, Department of General Surgery, HPB-Unit, School of Medicine, Istanbul, Türkei
,
Demir IE
1   Klinik und Poliklinik für Chirurgie, Klinikum r.d. Isar, TUM, München, Deutschland
› Author Affiliations
 

Neural invasion (NI) is an independent prognostic factor in many solid cancers, including pancreatic ductal adenocarcinoma and colorectal cancer.

To analyse the molecular players in the cross-talk of neuronal and pancreatic cancer cells, we used a novel generated mouse model showing NI pathology phenocopying patient PDAC samples. These mutants are comprised out of an overexpression transgene of Tgfa under the elastase1 promoter and the conditional deletion of the Trp53 and p65 genes in Ptfa positive pancreatic cells. Ex vivo, PDAC cells derived from TPAC mice showed greater intrinsic neuroaffinity in a migration assay compared to the other PDAC mutant lines.

We could show, that this phenotype was induced by the chemokine CCL2, whose secretion was dramatically upregulated by neurons, co-cultured with cancer cells. Moreover, CCL2 signalling via the CCR4 receptor induced phosphorylation of paxillin with subsequent rearrangement of the cytoskeleton in these cancer cells.

We found increased p-paxillin in cancer cells and increased CCL2 content in nerves in PDAC patient samples to be unfavourable prognostic markers for overall survival. Application of rCCL2 in KPC mice induced high cancer-nerve cell proximity, which was reduced after CCR4 inhibition. Furthermore, inhibition of paxillin phosphorylation with the inhibitor 6B345TTQ significantly reduced neuronal density in TPAC mice. In addition, tumour progression and metastasis of allografts generated by implantation of TPAC cancer cells into the pancreas is significantly reduced after treatment with the paxillin inhibitor.

The present study identified the neuron-triggered CCL2/CCR4/p-Paxillin pathway as a novel mechanism of neural invasion that offers a potential strategy for therapeutic intervention.



Publication History

Article published online:
07 September 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany