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NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung
Lydia Meder1,2,3,4, Katharina König1,2,3,4, Luka Ozretić1,2,3,4
1Institute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
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. Additionally, 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.
Insights
Researchers identified a new pathway driving secondary small cell lung cancer (SCLC) and other small cell carcinomas. This discovery sheds light on aggressive tumor development and potential therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Small cell lung cancers (SCLCs) and extrapulmonary small cell cancers (SCCs) are aggressive tumors often linked to RB1 and TP53 genetic lesions.
- While primary SCLC is thought to originate from neuroendocrine stem cells, secondary transitions from non-small cell carcinomas to neuroendocrine tumors also occur, particularly after therapy.
Purpose of the Study:
- To define the key features of 'small cell-ness' including neuroendocrine markers, RB1/TP53 mutations, and morphology.
- To identify the molecular pathway driving the pathogenesis of secondary SCLC and other small cell carcinomas.
- To explore therapeutic interventions targeting identified pathways, such as CDK5 inhibition.
Main Methods:
- Analysis of clinical tumor samples (SCLC, SCC, large cell neuroendocrine carcinomas, adenocarcinomas) using Next Generation Sequencing, immunohistochemistry, and fluorescence in situ hybridization.
- Experimental verification of the NOTCH-ASCL1-RB-p53 signaling axis in vitro.
- In vivo validation of pathway activation by genetic alterations.
Main Results:
- A novel pathway driving secondary SCLC pathogenesis was identified, involving NOTCH inactivation, ASCL1 activation, and WNT signaling, alongside RB1 and TP53 mutations.
- ASCL1-dependent RB inactivation via phosphorylation was observed and shown to be reversible by CDK5 inhibition.
- The identified signaling axis was experimentally verified and validated in clinical samples.
Conclusions:
- A new molecular pathway underlying rare secondary SCLCs has been discovered.
- This pathway may also drive small cell carcinomas in organs beyond the lung.
- Understanding this pathway offers potential for novel therapeutic strategies against aggressive small cell cancers.
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