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NOTCH , ASCL1 , p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas
Author(s) -
Meder Lydia,
König Katharina,
Ozretić Luka,
Schultheis Anne M.,
Ueckeroth Frank,
Ade Carsten P.,
Albus Kerstin,
Boehm Diana,
RommerscheidtFuss Ursula,
Florin Alexandra,
Buhl Theresa,
Hartmann Wolfgang,
Wolf Jürgen,
MerkelbachBruse Sabine,
Eilers Martin,
Perner Sven,
Heukamp Lukas C.,
Buettner Reinhard
Publication year - 2015
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29835
Subject(s) - wnt signaling pathway , biology , cancer research , notch signaling pathway , neuroendocrine differentiation , pathology , neuroendocrine cell , context (archaeology) , cell , cancer , signal transduction , immunohistochemistry , immunology , microbiology and biotechnology , medicine , genetics , paleontology , prostate cancer
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.