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NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas

2015-09-04 20:46:21

INTERNATIONAL JOURNAL OF CANCER; 4 September 2015: DOI:10.1002/ijc.29835


Yo Saito, Tohru Fujiwara, Keiichi Ohashi, Yoko Okitsu, Noriko Fukuhara, Yasushi Onishi, Kenichi Ishizawa, Hideo Harigae



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 analyze 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.



Introduction


The current WHO classification of lung cancer discriminates small cell lung cancer (SCLC) from non-small cell lung cancer (NSCLC) comprising the entities adenocarcinoma (AdC), squamous cell carcinoma (SqCC), a few rare subtypes of NSCLC, large cell neuroendocrine carcinoma (LCNEC), and finally typical and atypical
carcinoids. A novel genomics-based taxonomy of lung tumors proposed by the worldwide initiative of the Clinical Lung Cancer Genome Project (CLCGP) and the Network Genomic Medicine (NGM) suggests that a combination of histological and genomic denominators will redefine the classification into SCLC/LCNEC, AdC, SqCC and carcinoids.



SCLC has distinct pathological and clinical features. Tumor cells have round, spindled nuclei with finely granulated chromatin, inconspicuous nucleoli, scant cytoplasm, and frequently shows nuclear moulding. SCLCs have high mitotic rates (>60 mitoses per 2 mm²) and frequently a neuroendocrine (NE) phenotype. All small cell carcinomas (SCCs), however representing a rare tumor entity, share a very aggressive biology with early systemic spread, irrespective of organ of origin. Therefore, it is likely that general molecular mechanisms drive ‘small cell-ness’ with cancer stem cell-related features. We and others showed that mutual bi-allelic TP53 and RB1 alterations are central events in SCLC biology. Bi-allelic loss of TP53 and RB1 is sufficient to induce a SCC phenotype in murine lung tumors. Nevertheless, combined lung carcinoma phenotypes and relapses with a changed phenotype upon cancer therapy occur in patients. Thus, we suggest that NE SCCs may not only arise as primary lesions or as a synchronous combined carcinoma but also arise as secondary lesions in form of relapses originating from non-small cell carcinomas induced by cancer therapy.



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Key Words


Lung cancer | SCLC | ASCL1 | NOTCH | RB