ArticleNature2017
Intratumoural heterogeneity generated by Notch signalling promotes small-cell lung cancer.
Article in Nature, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 322 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
322 citing papers in PubMed, 1 synthesis or guideline pooled it, 485 citations in OpenAlex.
- A multiplexed in vivo approach to identify driver genes in small cell lung cancer.Cell reports · 2023Pooled it
- NOTCH1 reverses immune suppression in small cell lung cancer through reactivation of STING.The Journal of clinical investigation · 2025Trial
- Clinical Benefit From Immunotherapy in Patients With SCLC Is Associated With Tumor Capacity for Antigen Presentation.Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer · 2023Trial
- PAX5 modulates vascularization and contributes to neuroendocrine lineage transition during carcinoma progression.The Journal of clinical investigation · 2026Article
- SOX30 Facilitates Triple-Negative Breast Cancer Metastasis via TNFR2-NF-κB Signaling and Tumor Microenvironment Remodeling.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Article
- Integrating molecular subtypes, genomics and functional dependencies to identify context-specific therapeutic vulnerabilities in small cell lung cancer.Biomarker research · 2026Review
- Spindle Assembly Checkpoint Competency Determines Sensitivity to KIF18A Inhibition in Small Cell Lung Cancer.Cancer research communications · 2026Article
- Multi-omics profiling of recurrence-associated extrachromosomal circular DNA characteristics and its prognostic potential in lung adenocarcinoma.Precision clinical medicine · 2026Article
- Cancer Neuroscience: From Local Neuro-Immune Microenvironments to Systemic Brain-Body Circuitry.MedComm · 2026Review
- The neuronal network of small cell lung cancer: a narrative review of the role of the nervous system in the pathogenesis and progression.Translational lung cancer research · 2026Review
- Blockade of Tumor-Intrinsic TGFβ Signaling Drives Hyperprogression in Small Cell Lung Cancer.Cancer discovery · 2026Article
- Charting intratumor heterogeneity from bench to bedside.Nature cancer · 2026Review
- Transcriptional evidence of neuroendocrine cell plasticity beyond histological boundaries in lung neuroendocrine neoplasms: an in-silico analysis suggesting a progression model.Journal of experimental & clinical cancer research : CR · 2026Article
- Loss of the USP22 deubiquitylase confers resistance to chemotherapy in small cell lung cancer.Nature communications · 2026Article
- Adoptive cell therapies in thoracic malignancies: a comprehensive review.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Mechanisms of resistance in small cell lung cancer.Chinese medical journal · 2026Review
- Article
- Molecular phenotypes stratify small cell lung cancer for targeted therapy and immunotherapy.British journal of cancer · 2026Article
- Pan-Cancer Prognostic Analysis of NMDAR Genes Discovered Therapeutic Implications of Neuronal-Cancer Crosstalk Mediator GRIN2A for Small Cell Lung Cancer.Biomedicines · 2026Article
262 more citing papers are in PubMed but not listed here.
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Authors and funding
20 authors at 4 institutions in 2 countries.
Funding
Abstract
The Notch signalling pathway mediates cell fate decisions and is tumour suppressive or oncogenic depending on the context. During lung development, Notch pathway activation inhibits the differentiation of precursor cells to a neuroendocrine fate. In small-cell lung cancer, an aggressive neuroendocrine lung cancer, loss-of-function mutations in NOTCH genes and the inhibitory effects of ectopic Notch activation indicate that Notch signalling is tumour suppressive. Here we show that Notch signalling can be both tumour suppressive and pro-tumorigenic in small-cell lung cancer. Endogenous activation of the Notch pathway results in a neuroendocrine to non-neuroendocrine fate switch in 10-50% of tumour cells in a mouse model of small-cell lung cancer and in human tumours. This switch is mediated in part by Rest (also known as Nrsf), a transcriptional repressor that inhibits neuroendocrine gene expression. Non-neuroendocrine Notch-active small-cell lung cancer cells are slow growing, consistent with a tumour-suppressive role for Notch, but these cells are also relatively chemoresistant and provide trophic support to neuroendocrine tumour cells, consistent with a pro-tumorigenic role. Importantly, Notch blockade in combination with chemotherapy suppresses tumour growth and delays relapse in pre-clinical models. Thus, small-cell lung cancer tumours generate their own microenvironment via activation of Notch signalling in a subset of tumour cells, and the presence of these cells may serve as a biomarker for the use of Notch pathway inhibitors in combination with chemotherapy in select patients with small-cell lung cancer.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.