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

Autor: Hedegger K; Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU München, Germany., Blutke A; Institute of Veterinary Pathology, Center for Clinical Veterinary Medicine, LMU München, Germany., Hommel T; Institute of in vivo and in vitro Models, University of Veterinary Medicine, Vienna, Austria., Auer KE; Institute of in vivo and in vitro Models, University of Veterinary Medicine, Vienna, Austria., Nataraj NB; Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel.; Bugworks Research Inc, CCAMP, Bengaluru, India., Lindzen M; Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel., Yarden Y; Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel., Dahlhoff M; Institute of in vivo and in vitro Models, University of Veterinary Medicine, Vienna, Austria.
Jazyk: angličtina
Zdroj: Molecular oncology [Mol Oncol] 2023 Nov; Vol. 17 (11), pp. 2415-2431. Date of Electronic Publication: 2023 Jul 14.
DOI: 10.1002/1878-0261.13473
Abstrakt: 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-F C , comprising the ligand-binding domains of both EGFR and ERBB4 and able to trap all ERBB ligands. Next, we generated a transgenic mouse model (CBA TRAP/0 ) expressing TRAP-F C ubiquitously under the control of the chicken-beta-actin promoter and crossed these mice with KRAS G12D/+ 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.
(© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
Externí odkaz: