Universität zu Köln

Meder, Lydia, Florin, Alexandra, Ozretic, Luka, Nill, Marieke, Koker, Mirjam, Meemboor, Sonja, Radtke, Freddy, Diehl, Linda, Ullrich, Roland T., Odenthal, Margarete, Buettner, Reinhard and Heukamp, Lukas C. (2021). Notch1 Deficiency Induces Tumor Cell Accumulation Inside the Bronchiolar Lumen and Increases TAZ Expression in an Autochthonous Kras (LSL-G12V) Driven Lung Cancer Mouse Model. Pathol. Oncol. Res., 27. LAUSANNE: FRONTIERS MEDIA SA. ISSN 1532-2807

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Abstract

Purpose: Abrogation of Notch signaling, which is pivotal for lung development and pulmonary epithelial cell fate decisions was shown to be involved in the aggressiveness and the differentiation of lung carcinomas. Additionally, the transcription factors YAP and TAZ which are involved in the Hippo pathway, were recently shown to be tightly linked with Notch signaling and to regulate the cell fate in epidermal stem cells. Thus, we aim to elucidate the effects of conditional Notch1 deficiency on carcinogenesis and TAZ expression in lung cancer. Methods: We investigated the effect of conditional Cre-recombinase mediated Notch1 knock-out on lung cancer cells in vivo using an autochthonous mouse model of lung adenocarcinomas driven by Kras (LSL-G12V) and comprehensive immunohistochemical analysis. In addition, we analyzed clinical samples and human lung cancer cell lines for TAZ expression and supported our findings by publicly available data from The Cancer Genome Atlas (TCGA). Results: In mice, we found induction of papillary adenocarcinomas and protrusions of tumor cells from the bronchiolar lining upon Notch1 deficiency. Moreover, the mutated Kras driven lung tumors with deleted Notch1 showed increased TAZ expression and focal nuclear translocation which was frequently observed in human pulmonary adenocarcinomas and squamous cell carcinomas of the lung, but not in small cell lung carcinomas. In addition, we used data from TCGA to show that putative inactivating NOTCH1 mutations co-occur with KRAS mutations and genomic amplifications in lung adenocarcinomas. Conclusion: Our in vivo study provides evidence that Notch1 deficiency in mutated Kras driven lung carcinomas contributes to lung carcinogenesis in a subgroup of patients by increasing TAZ expression who might benefit from TAZ signaling blockade.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Meder, Lydia UNSPECIFIED UNSPECIFIED UNSPECIFIED Florin, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Ozretic, Luka UNSPECIFIED UNSPECIFIED UNSPECIFIED Nill, Marieke UNSPECIFIED UNSPECIFIED UNSPECIFIED Koker, Mirjam UNSPECIFIED UNSPECIFIED UNSPECIFIED Meemboor, Sonja UNSPECIFIED UNSPECIFIED UNSPECIFIED Radtke, Freddy UNSPECIFIED UNSPECIFIED UNSPECIFIED Diehl, Linda UNSPECIFIED UNSPECIFIED UNSPECIFIED Ullrich, Roland T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Odenthal, Margarete UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Heukamp, Lukas C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-597135
DOI:	10.3389/pore.2021.596522
Journal or Publication Title:	Pathol. Oncol. Res.
Volume:	27
Date:	2021
Publisher:	FRONTIERS MEDIA SA
Place of Publication:	LAUSANNE
ISSN:	1532-2807
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HIPPO TRANSDUCER TAZ; SQUAMOUS-CELL; YAP/TAZ; ADENOCARCINOMA; CLASSIFICATION; NEUROENDOCRINE; ORIGIN; LEADS Multiple languages Oncology; Pathology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59713