Title (en)
Trapping all ERBB ligands decreases pancreatic lesions in a murine model of pancreatic ductal adenocarcinoma
Language
English
Description (en)
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest of cancers. Attempts to develop targeted therapies still need to be established. Some oncogenic mechanisms in PDAC carcinogenesis harness the EGFR/ERBB receptor family. To explore the effects on pancreatic lesions, we attempted simultaneous blockade of all ERBB ligands in a PDAC mouse model. To this end, we engineered a molecular decoy, TRAP-FC , comprising the ligand-binding domains of both EGFR and ERBB4 and able to trap all ERBB ligands. Next, we generated a transgenic mouse model (CBATRAP/0 ) expressing TRAP-FC ubiquitously under the control of the chicken-beta-actin promoter and crossed these mice with KRASG12D/+ mice (Kras) to generate Trap/Kras mice. The resulting mice displayed decreased emergence of spontaneous pancreatic lesion areas and exhibited reduced RAS activity and decreased activities of ERBBs, with the exception of ERBB4, which showed increased activity. To identify the involved receptor(s), we employed CRISPR/Cas9 DNA editing to singly delete each ERBB receptor in the human pancreatic carcinoma cell line Panc-1. Ablation of each ERBB family member, especially the loss of EGFR or ERBB2/HER2, altered signaling downstream of the other three ERBB receptors and decreased cell proliferation, migration, and tumor growth. We conclude that simultaneously blocking the entire ERBB receptor family is therapeutically more effective than individually inhibiting only one receptor or ligand in terms of reducing pancreatic tumor burden. In summary, trapping all ERBB ligands can reduce pancreatic lesion area and RAS activity in a murine model of pancreatic adenocarcinoma; hence, it might represent a promising approach to treat PDAC in patients.
Keywords (en)
Mice; Humans; Animals; Pancreatic Neoplasmspathology; Proto-Oncogene Proteins p21(ras)geneticsmetabolism; Adenocarcinoma; Disease Models, Animal; Ligands; Mice, Inbred CBA; Carcinoma, Pancreatic Ductalpathology; Mice, Transgenic; Receptor, ErbB-4metabolism
DOI
10.1002/1878-0261.13473
Author of the digital object
Kathrin Hedegger  (Ludwig Maximilian University of Munich)
Maik Dahlhoff  (University of Veterinary Medicine Vienna)
Yosef Yarden  (Weizmann Institute of Science)
Moshit Lindzen  (Weizmann Institute of Science)
Nishanth B. Nataraj  (Weizmann Institute of Science / Bugworks Research Inc)
Kerstin E. Auer  (University of Veterinary Medicine Vienna)
Theresa Hommel  (University of Veterinary Medicine Vienna)
Andreas Blutke  (Ludwig Maximilian University of Munich)
Format
application/pdf
Size
1.2 MB
Licence Selected
CC BY 4.0 International
Type of publication
Article
Name of Publication (en)
Molecular Oncology
Pages or Volume
17
Volume
17
Number
11
From Page
2415
To Page
2431
Publisher
Wiley
Publication Date
2023