المؤلفون: Hedegger, Kathrin, Blutke, Andreas, Hommel, Theresa, Auer, Kerstin E., Nataraj, Nishanth B., Lindzen, Moshit, Yarden, Yosef, Dahlhoff, Maik

المصدر: Molecular Oncology; Nov2023, Vol. 17 Issue 11, p2415-2431, 17p

مستخلص: 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. [ABSTRACT FROM AUTHOR]

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المؤلفون: Tropitzsch, Anke, Schade-Mann, Thore, Gamerdinger, Philipp, Dofek, Saskia, Schulte, Björn, Schulze, Martin, Fehr, Sarah, Biskup, Saskia, Haack, Tobias B., Stöbe, Petra, Heyd, Andreas, Harre, Jennifer, Lesinski-Schiedat, Anke, Büchner, Andreas, Lenarz, Thomas, Warnecke, Athanasia, Müller, Marcus, Vona, Barbara, Dahlhoff, Ernst, Löwenheim, Hubert, Holderried, Martin

المصدر: Ear and Hearing; November-December 2023, Vol. 44 Issue: 6 p1464-1484, 21p

المؤلفون: Willmann, Michael, Peter, Barbara, Slavnitsch, Katharina, Berger, Daniela, Witzeneder, Nadine, Stefanzl, Gabriele, Eisenwort, Gregor, Ivanov, Daniel, Sadovnik, Irina, Hadzijusufovic, Emir, Greiner, Georg, Bernthaler, Tina, Hoermann, Gregor, Dahlhoff, Maik, Rülicke, Thomas, Valent, Peter

المصدر: Leukemia; May 2023, Vol. 37 Issue: 5 p1162-1165, 4p

المؤلفون: Geyer, Laura J., Janssen, Klaus-Peter, Dahlhoff, Maik

المصدر: Gastroenterology (00165085); 2024 Supplement, Vol. 166 Issue 5, pS-390-S-391, 1p

المؤلفون: Hoesl, Christine, Fröhlich, Thomas, Posch, Christian, Kneitz, Hermann, Goebeler, Matthias, Schneider, Marlon R., Dahlhoff, Maik

المصدر: Molecular Oncology; Aug2021, Vol. 15 Issue 8, p2140-2155, 16p

مستخلص: The incidence of melanoma and nonmelanoma skin cancer has increased tremendously in recent years. Although novel treatment options have significantly improved patient outcomes, the prognosis for most patients with an advanced disease remains dismal. It is, thus, imperative to understand the molecular mechanisms involved in skin carcinogenesis in order to develop new targeted treatment strategies. Receptor tyrosine kinases (RTK) like the ERBB receptor family, including EGFR/ERBB1, ERBB2/NEU, ERBB3, and ERBB4, are important regulators of skin homeostasis and their dysregulation often results in cancer, which makes them attractive therapeutic targets. Members of the leucine‐rich repeats and immunoglobulin‐like domains protein family (LRIG1‐3) are ERBB regulators and thus potential therapeutic targets to manipulate ERBB receptors. Here, we analyzed the function of LRIG1 during chemically induced skin carcinogenesis in transgenic mice expressing LRIG1 in the skin under the control of the keratin 5 promoter (LRIG1‐TG mice). We observed a significant induction of melanocytic tumor formation in LRIG1‐TG mice and no difference in papilloma incidence between LRIG1‐TG and control mice. Our findings also revealed that LRIG1 affects ERBB signaling via decreased phosphorylation of EGFR and increased activation of the oncoprotein ERBB2 during skin carcinogenesis. The epidermal proliferation rate was significantly decreased during epidermal tumorigenesis under LRIG1 overexpression, and the apoptosis marker cleaved caspase 3 was significantly activated in the epidermis of transgenic LRIG1 mice. Additionally, we detected LRIG1 expression in human cutaneous squamous cell carcinoma and melanoma samples. Therefore, we depleted LRIG1 in human melanoma cells (A375) by CRISPR/Cas9 technology and found that this caused EGFR and ERBB3 downregulation in A375 LRIG1 knockout cells 6 h following stimulation with EGF. In conclusion, our study demonstrated that LRIG1‐TG mice develop melanocytic skin tumors during chemical skin carcinogenesis and a deletion of LRIG1 in human melanoma cells reduces EGFR and ERBB3 expression after EGF stimulation. [ABSTRACT FROM AUTHOR]

: Copyright of Molecular Oncology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Hedegger, Kathrin, Algül, Hana, Lesina, Marina, Blutke, Andreas, Schmid, Roland M., Schneider, Marlon R., Dahlhoff, Maik

المصدر: Molecular Oncology; Aug2020, Vol. 14 Issue 8, p1653-1669, 17p

مستخلص: 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. [ABSTRACT FROM AUTHOR]

: Copyright of Molecular Oncology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Frey, Laura, Ziętara, Natalia, Łyszkiewicz, Marcin, Marquardt, Benjamin, Mizoguchi, Yoko, Linder, Monika I., Liu, Yanshan, Giesert, Florian, Wurst, Wolfgang, Dahlhoff, Maik, Schneider, Marlon R., Wolf, Eckhard, Somech, Raz, Klein, Christoph

المصدر: Blood; April 2021, Vol. 137 Issue: 14 p1932-1944, 13p

مستخلص: Vacuolar protein sorting 45 homolog (VPS45), a member of the Sec1/Munc18 (SM) family, has been implicated in the regulation of endosomal trafficking. VPS45 deficiency in human patients results in congenital neutropenia, bone marrow fibrosis, and extramedullary renal hematopoiesis. Detailed mechanisms of the VPS45 function are unknown. Here, we show an essential role of mammalian VPS45 in maintaining the intracellular organization of endolysosomal vesicles and promoting recycling of cell-surface receptors. Loss of VPS45 causes defective Rab5-to-Rab7 conversion resulting in trapping of cargos in early endosomes and impaired delivery to lysosomes. In this context, we demonstrate aberrant trafficking of the granulocyte colony-stimulating factor receptor in the absence of VPS45. Furthermore, we find that lack of VPS45 in mice is not compatible with embryonic development. Thus, we identify mammalian VPS45 as a critical regulator of trafficking through the endosomal system and early embryogenesis of mice.

المؤلفون: Frey, Laura, Ziętara, Natalia, Łyszkiewicz, Marcin, Marquardt, Benjamin, Mizoguchi, Yoko, Linder, Monika I., Liu, Yanshan, Giesert, Florian, Wurst, Wolfgang, Dahlhoff, Maik, Schneider, Marlon R., Wolf, Eckhard, Somech, Raz, Klein, Christoph

المصدر: Blood; April 2021, Vol. 137 Issue: 14 p1932-1944, 13p

مستخلص: Vacuolar protein sorting 45 homolog (VPS45), a member of the Sec1/Munc18 (SM) family, has been implicated in the regulation of endosomal trafficking. VPS45 deficiency in human patients results in congenital neutropenia, bone marrow fibrosis, and extramedullary renal hematopoiesis. Detailed mechanisms of the VPS45 function are unknown. Here, we show an essential role of mammalian VPS45 in maintaining the intracellular organization of endolysosomal vesicles and promoting recycling of cell-surface receptors. Loss of VPS45 causes defective Rab5-to-Rab7 conversion resulting in trapping of cargos in early endosomes and impaired delivery to lysosomes. In this context, we demonstrate aberrant trafficking of the granulocyte colony-stimulating factor receptor in the absence of VPS45. Furthermore, we find that lack of VPS45 in mice is not compatible with embryonic development. Thus, we identify mammalian VPS45 as a critical regulator of trafficking through the endosomal system and early embryogenesis of mice.

المؤلفون: Hoesl, Christine, Fröhlich, Thomas, Hundt, Jennifer E., Kneitz, Hermann, Goebeler, Matthias, Wolf, Ronald, Schneider, Marlon R., Dahlhoff, Maik

المصدر: Molecular Oncology; Nov2019, Vol. 13 Issue 11, p2476-2492, 17p

مستخلص: Over the last few decades, the number of cases of non‐melanoma skin cancer (NMSC) has risen to over 3 million cases every year worldwide. Members of the ERBB receptor family are important regulators of skin development and homeostasis and, when dysregulated, contribute to skin pathogenesis. In this study, we investigated leucine‐rich repeats and immunoglobulin‐like domains 2 (LRIG2), a transmembrane protein involved in feedback loop regulation of the ERBB receptor family during NMSC. LRIG2 was identified to be up‐regulated in various types of squamous cell carcinoma (SCC), but little is known about LRIG2 in cutaneous SCC (cSCC). To investigate the function of LRIG2 in cSCC in vivo, we generated a skin‐specific LRIG2 overexpressing transgenic mouse line (LRIG2‐TG) using the Tet‐Off system. We employed the 7,12‐dimethylbenz(a)anthracene/12‐O‐tetra‐decanoylphorbol‐13‐acetate (DMBA/TPA) two‐stage chemical carcinogenesis model and analyzed the skin during homeostasis and tumorigenesis. LRIG2‐TG mice did not exhibit alterations in skin development or homeostasis but showed an interaction between LRIG2 and thrombospondin‐1, which is often involved in angiogenesis and tumorigenesis. However, during carcinogenesis, transgenic animals showed significantly increased tumor progression and a more rapid development of cSCC. This was accompanied by changes in the ERBB system. After a single TPA application, inflammation of the epidermis was enhanced during LRIG2 overexpression. In human skin samples, LRIG2 expression was identified in the basal layer of the epidermis and in hair follicles of normal skin, but also in cSCC samples. In conclusion, epidermal LRIG2 excess is associated with activated EGFR/ERBB4‐MAPK signaling and accelerated tumor progression in experimentally induced NMSC, suggesting LRIG2 as a potential oncoprotein in skin. [ABSTRACT FROM AUTHOR]

: Copyright of Molecular Oncology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Backman, Mattias, Flenkenthaler, Florian, Blutke, Andreas, Dahlhoff, Maik, Ländström, Erik, Renner, Simone, Philippou-Massier, Julia, Krebs, Stefan, Rathkolb, Birgit, Prehn, Cornelia, Grzybek, Michal, Coskun, Ünal, Rothe, Michael, Adamski, Jerzy, de Angelis, Martin Hrabĕ, Wanke, Rüdiger, Fröhlich, Thomas, Arnold, Georg J., Blum, Helmut, Wolf, Eckhard

المصدر: Molecular Metabolism; Aug2019, Vol. 26, p30-44, 15p

مستخلص: The liver regulates the availability of insulin to other tissues and is the first line insulin response organ physiologically exposed to higher insulin concentrations than the periphery. Basal insulin during fasting inhibits hepatic gluconeogenesis and glycogenolysis, whereas postprandial insulin peaks stimulate glycogen synthesis. The molecular consequences of chronic insulin deficiency for the liver have not been studied systematically. We analyzed liver samples of a genetically diabetic pig model (MIDY) and of wild-type (WT) littermate controls by RNA sequencing, proteomics, and targeted metabolomics/lipidomics. Cross-omics analyses revealed increased activities in amino acid metabolism, oxidation of fatty acids, ketogenesis, and gluconeogenesis in the MIDY samples. In particular, the concentrations of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) and of retinol dehydrogenase 16 (RDH16), which catalyzes the first step in retinoic acid biogenesis, were highly increased. Accordingly, elevated levels of retinoic acid, which stimulates the expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PCK1), were measured in the MIDY samples. In contrast, pathways related to extracellular matrix and inflammation/pathogen defense response were less active than in the WT samples. The first multi-omics study of a clinically relevant diabetic large animal model revealed molecular signatures and key drivers of functional alterations of the liver in insulin-deficient diabetes mellitus. The multi-omics data set provides a valuable resource for comparative analyses with other experimental or clinical data sets. • MIDY pigs were used to study consequences of insulin-deficient diabetes for the liver. • RDH16 and HMGCS2 were drivers of stimulated gluconeogenesis and ketogenesis in MIDY pigs. • Hepatic immune functions and extracellular matrix were reduced in MIDY pigs. • This multi-omics data resource is valuable for analyses of other liver omics data sets. [ABSTRACT FROM AUTHOR]

: Copyright of Molecular Metabolism is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)