Titel (eng)

Trapping all ERBB ligands decreases pancreatic lesions in a murine model of pancreatic ductal adenocarcinoma

Autor*in

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

Verlag

Wiley

Beschreibung (eng)

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.

Sprache des Objekts

Englisch

Datum

2023

Rechte

Dieses Werk bzw. dieser Inhalt steht unter einer
CC BY 4.0 - Creative Commons Namensnennung 4.0 International Lizenz.

CC BY 4.0 International

http://creativecommons.org/licenses/by/4.0/

Klassifikation

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

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