Unraveling ERBB network dynamics upon betacellulin signaling in pancreatic ductal adenocarcinoma in mice
Pancreatic ductal adenocarcinoma (PDAC) will soon belong to the top three cancer killers. The only approved specific PDAC therapy targets the epidermal growth factor receptor (EGFR). Although EGFR is a crucial player in PDAC development, EGFR‐based therapy is disappointing. In this study, we evaluat...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-08-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.12699 |
| _version_ | 1818336458978623488 |
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| author | Kathrin Hedegger Hana Algül Marina Lesina Andreas Blutke Roland M. Schmid Marlon R. Schneider Maik Dahlhoff |
| author_facet | Kathrin Hedegger Hana Algül Marina Lesina Andreas Blutke Roland M. Schmid Marlon R. Schneider Maik Dahlhoff |
| author_sort | Kathrin Hedegger |
| collection | DOAJ |
| description | Pancreatic ductal adenocarcinoma (PDAC) will soon belong to the top three cancer killers. The only approved specific PDAC therapy targets the epidermal growth factor receptor (EGFR). Although EGFR is a crucial player in PDAC development, EGFR‐based therapy is disappointing. In this study, we evaluated the role of the EGFR ligand betacellulin (BTC) in PDAC. The expression of BTC was investigated in human pancreatic cancer specimen. Then, we generated a BTC knockout mouse model by CRISPR/Cas9 technology and a BTC overexpression model. Both models were crossed with the Ptf1aCre/+;KRASG12D/+ (KC) mouse model (B−/−KC or BKC, respectively). In addition, EGFR, ERBB2, and ERBB4 were investigated by the pancreas‐specific deletion of each receptor using the Cre‐loxP system. Tumor initiation and progression were analyzed in all mouse lines, and the underlying molecular biology of PDAC was investigated at different time points. BTC is expressed in human and murine PDAC. B−/−KC mice showed a decelerated PDAC progression, associated with decreased EGFR activation. BKC mice developed severe PDAC with a poor survival rate. The dramatically increased BTC‐mediated tumor burden was EGFR‐dependent, but also ERBB4 and ERBB2 were involved in PDAC development or progression, as depletion of EGFR, ERBB2, or ERBB4 significantly improved the survival rate of BTC‐mediated PDAC. BTC increases PDAC tumor burden dramatically by enhanced RAS activation. EGFR signaling, ERBB2 signaling, and ERBB4 signaling are involved in accelerated PDAC development mediated by BTC indicating that targeting the whole ERBB family, instead of a single receptor, is a promising strategy for the development of future PDAC therapies. |
| first_indexed | 2024-12-13T14:39:39Z |
| format | Article |
| id | doaj.art-1db56fa19d1346b68d5beccc22c8c382 |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-12-13T14:39:39Z |
| publishDate | 2020-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-1db56fa19d1346b68d5beccc22c8c3822022-12-21T23:41:38ZengWileyMolecular Oncology1574-78911878-02612020-08-011481653166910.1002/1878-0261.12699Unraveling ERBB network dynamics upon betacellulin signaling in pancreatic ductal adenocarcinoma in miceKathrin Hedegger0Hana Algül1Marina Lesina2Andreas Blutke3Roland M. Schmid4Marlon R. Schneider5Maik Dahlhoff6Institute of Molecular Animal Breeding and Biotechnology Gene Center of the LMU Munich GermanySecond Department of Internal Medicine Klinikum rechts der Isar Technical University of Munich GermanySecond Department of Internal Medicine Klinikum rechts der Isar Technical University of Munich GermanyResearch Unit Analytical Pathology Helmholtz Zentrum München Neuherberg GermanySecond Department of Internal Medicine Klinikum rechts der Isar Technical University of Munich GermanyInstitute of Molecular Animal Breeding and Biotechnology Gene Center of the LMU Munich GermanyInstitute of Molecular Animal Breeding and Biotechnology Gene Center of the LMU Munich GermanyPancreatic ductal adenocarcinoma (PDAC) will soon belong to the top three cancer killers. The only approved specific PDAC therapy targets the epidermal growth factor receptor (EGFR). Although EGFR is a crucial player in PDAC development, EGFR‐based therapy is disappointing. In this study, we evaluated the role of the EGFR ligand betacellulin (BTC) in PDAC. The expression of BTC was investigated in human pancreatic cancer specimen. Then, we generated a BTC knockout mouse model by CRISPR/Cas9 technology and a BTC overexpression model. Both models were crossed with the Ptf1aCre/+;KRASG12D/+ (KC) mouse model (B−/−KC or BKC, respectively). In addition, EGFR, ERBB2, and ERBB4 were investigated by the pancreas‐specific deletion of each receptor using the Cre‐loxP system. Tumor initiation and progression were analyzed in all mouse lines, and the underlying molecular biology of PDAC was investigated at different time points. BTC is expressed in human and murine PDAC. B−/−KC mice showed a decelerated PDAC progression, associated with decreased EGFR activation. BKC mice developed severe PDAC with a poor survival rate. The dramatically increased BTC‐mediated tumor burden was EGFR‐dependent, but also ERBB4 and ERBB2 were involved in PDAC development or progression, as depletion of EGFR, ERBB2, or ERBB4 significantly improved the survival rate of BTC‐mediated PDAC. BTC increases PDAC tumor burden dramatically by enhanced RAS activation. EGFR signaling, ERBB2 signaling, and ERBB4 signaling are involved in accelerated PDAC development mediated by BTC indicating that targeting the whole ERBB family, instead of a single receptor, is a promising strategy for the development of future PDAC therapies.https://doi.org/10.1002/1878-0261.12699BTCEGFRERBB2ERBB4mouse modelPDAC |
| spellingShingle | Kathrin Hedegger Hana Algül Marina Lesina Andreas Blutke Roland M. Schmid Marlon R. Schneider Maik Dahlhoff Unraveling ERBB network dynamics upon betacellulin signaling in pancreatic ductal adenocarcinoma in mice Molecular Oncology BTC EGFR ERBB2 ERBB4 mouse model PDAC |
| title | Unraveling ERBB network dynamics upon betacellulin signaling in pancreatic ductal adenocarcinoma in mice |
| title_full | Unraveling ERBB network dynamics upon betacellulin signaling in pancreatic ductal adenocarcinoma in mice |
| title_fullStr | Unraveling ERBB network dynamics upon betacellulin signaling in pancreatic ductal adenocarcinoma in mice |
| title_full_unstemmed | Unraveling ERBB network dynamics upon betacellulin signaling in pancreatic ductal adenocarcinoma in mice |
| title_short | Unraveling ERBB network dynamics upon betacellulin signaling in pancreatic ductal adenocarcinoma in mice |
| title_sort | unraveling erbb network dynamics upon betacellulin signaling in pancreatic ductal adenocarcinoma in mice |
| topic | BTC EGFR ERBB2 ERBB4 mouse model PDAC |
| url | https://doi.org/10.1002/1878-0261.12699 |
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