Universität zu Köln

Meder, Lydia ORCID: 0000-0002-9547-5812, Koenig, Katharina, Ozretic, Luka, Schultheis, Anne M., Ueckeroth, Frank, Ade, Carsten P., Albus, Kerstin, Boehm, Diana, Rommerscheidt-Fuss, Ursula, Florin, Alexandra, Buhl, Theresa, Hartmann, Wolfgang ORCID: 0000-0002-7609-5021, Wolf, Juergen, Merkelbach-Bruse, Sabine, Eilers, Martin, Perner, Sven, Heukamp, Lukas C. and Buettner, Reinhard (2016). NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas. Int. J. Cancer, 138 (4). S. 927 - 939. HOBOKEN: WILEY. ISSN 1097-0215

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Abstract

Small cell lung cancers (SCLCs) and extrapulmonary small cell cancers (SCCs) are very aggressive tumors arising de novo as primary small cell cancer with characteristic genetic lesions in RB1 and TP53. Based on murine models, neuroendocrine stem cells of the terminal bronchioli have been postulated as the cellular origin of primary SCLC. However, both in lung and many other organs, combined small cell/non-small cell tumors and secondary transitions from non-small cell carcinomas upon cancer therapy to neuroendocrine and small cell tumors occur. We define features of small cell-ness based on neuroendocrine markers, characteristic RB1 and TP53 mutations and small cell morphology. Furthermore, here we identify a pathway driving the pathogenesis of secondary SCLC involving inactivating NOTCH mutations, activation of the NOTCH target ASCL1 and canonical WNT-signaling in the context of mutual bi-allelic RB1 and TP53 lesions. Additionaly, we explored ASCL1 dependent RB inactivation by phosphorylation, which is reversible by CDK5 inhibition. We experimentally verify the NOTCH-ASCL1-RB-p53 signaling axis in vitro and validate its activation by genetic alterations in vivo. We analyzed clinical tumor samples including SCLC, SCC and pulmonary large cell neuroendocrine carcinomas and adenocarcinomas using amplicon-based Next Generation Sequencing, immunohistochemistry and fluorescence in situ hybridization. In conclusion, we identified a novel pathway underlying rare secondary SCLC which may drive small cell carcinomas in organs other than lung, as well.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Meder, Lydia UNSPECIFIED orcid.org/0000-0002-9547-5812 UNSPECIFIED Koenig, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Ozretic, Luka UNSPECIFIED UNSPECIFIED UNSPECIFIED Schultheis, Anne M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ueckeroth, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Ade, Carsten P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Albus, Kerstin UNSPECIFIED UNSPECIFIED UNSPECIFIED Boehm, Diana UNSPECIFIED UNSPECIFIED UNSPECIFIED Rommerscheidt-Fuss, Ursula UNSPECIFIED UNSPECIFIED UNSPECIFIED Florin, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Buhl, Theresa UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartmann, Wolfgang UNSPECIFIED orcid.org/0000-0002-7609-5021 UNSPECIFIED Wolf, Juergen UNSPECIFIED UNSPECIFIED UNSPECIFIED Merkelbach-Bruse, Sabine UNSPECIFIED UNSPECIFIED UNSPECIFIED Eilers, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Perner, Sven UNSPECIFIED UNSPECIFIED UNSPECIFIED Heukamp, Lukas C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-284580
DOI:	10.1002/ijc.29835
Journal or Publication Title:	Int. J. Cancer
Volume:	138
Number:	4
Page Range:	S. 927 - 939
Date:	2016
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1097-0215
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TRANSCRIPTION FACTOR; PREDICT SURVIVAL; CANCER; DIFFERENTIATION; EXPRESSION; GENE; INACTIVATION; PROTEIN; PHOSPHORYLATION; ADENOCARCINOMA Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/28458