MYC Drives Temporal Evolution of Small Cell Lung Cancer Subtypes by Reprogramming Neuroendocrine Fate

Ireland, Abbie S.; Micinski, Alexi M.; Kastner, David W.; Guo, Bingqian; Wait, Sarah J.; Spainhower, Kyle B.; Conley, Christopher J.; Chen, Opal S.; Guthrie, Matthew R.; Soltero, Danny; Qiao, Yi; Huang, Xiaomeng; Tarapcsák, Szabolcs; Devarakonda, Siddhartha; Chalishazar, Milind D.; Gertz, Jason; Moser, Justin; Marth, Gábor; Puri, Sonam; Witt, Benjamin L.; Spike, Benjamin T.; Oliver, Trudy G.

doi:10.1016/j.ccell.2020.05.001

Cited by 340 publications

(526 citation statements)

References 82 publications

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“…CDB analyses are shown in Figure 2 for MYC , which is commonly amplified and drives proliferation of SCLC ( Ireland et al, 2020 ), for BCL2 , which encodes a canonical antiapoptotic protein targeted by navitoclax (ABT-263) ( Rudin et al, 2012 ), and for two SCLC drugs, etoposide and topotecan. MYC amplification (in NCI) is correlated with its overexpression (by RNA-seq in CCLE) ( Figure 2D ).…”

Section: Resultsmentioning

confidence: 99%

“…With SCLC-Global, ~80% of the SCLC cell lines highly express one of the MYC genes, and MYC and MYCL are most prevalent ( Figure 4H ). Expression of the MYC genes is mutually exclusive ( Ireland et al, 2020 ; Mollaoglu et al, 2017 ), with the non-NE cell lines (Y and P) expressing MYC and the NE cell lines expressing MYCL and MYCN ( Figures 4H and S3 ).…”

Section: Resultsmentioning

confidence: 99%

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SCLC-CellMiner: A Resource for Small Cell Lung Cancer Cell Line Genomics and Pharmacology Based on Genomic Signatures

et al. 2020

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SUMMARY CellMiner-SCLC ( https://discover.nci.nih.gov/SclcCellMinerCDB/ ) integrates drug sensitivity and genomic data, including high-resolution methylome and transcriptome from 118 patient-derived small cell lung cancer (SCLC) cell lines, providing a resource for research into this “recalcitrant cancer.” We demonstrate the reproducibility and stability of data from multiple sources and validate the SCLC consensus nomenclature on the basis of expression of master transcription factors NEUROD1, ASCL1, POU2F3, and YAP1. Our analyses reveal transcription networks linking SCLC subtypes with MYC and its paralogs and the NOTCH and HIPPO pathways. SCLC subsets express specific surface markers, providing potential opportunities for antibody-based targeted therapies. YAP1-driven SCLCs are notable for differential expression of the NOTCH pathway, epithelial-mesenchymal transition (EMT), and antigen-presenting machinery (APM) genes and sensitivity to mTOR and AKT inhibitors. These analyses provide insights into SCLC biology and a framework for future investigations into subtype-specific SCLC vulnerabilities.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

SCLC-CellMiner: A Resource for Small Cell Lung Cancer Cell Line Genomics and Pharmacology Based on Genomic Signatures

et al. 2020

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“…In this study, we examined NE properties of patient-derived SCLC cell lines, PDXs and human tumors based on NE scores estimated from a gene expression signature. Currently, it is believed that Notch activation drives the lineage transition from ASCL1+ to NEUROD1+ to YAP1+ subtype (55) whereas POU2F3+ SCLC is a standalone subtype originated from tuft cells (56). While we observed mutually exclusive patterns of ASCL1 and NEUROD1 expression in cell lines, their co-expression was identified in many patient tumors.…”

Section: Discussionmentioning

confidence: 99%

Relationship Between Neuroendocrine and Immune Gene Expression in Small Cell Lung Cancer

Cai

Liu

Huang

et al. 2020

Preprint

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Small cell lung cancer (SCLC) is classified as a high-grade neuroendocrine (NE) tumor, but a subset of SCLC has been termed “variant” due to the loss of NE characteristics. In this study, we computed NE scores for patient-derived SCLC cell lines and xenografts, as well as human tumors. We aligned NE properties with transcription factor-defined molecular subtypes. Then we investigated the different immune phenotypes associated with high and low NE scores. We found repression of immune response genes as a shared feature between classic SCLC and pulmonary neuroendocrine cells of the healthy lung. With loss of NE fate, variant SCLC tumors regain cell-autonomous immune gene expression and exhibit higher tumor-immune interactions. Pan-cancer analysis revealed this NE lineage-specific immune phenotype in other cancers. Additionally, we observed MHC I re-expression in SCLC upon development of chemoresistance. These findings provide a new framework to guide design of treatment regimens in SCLC.

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“…Intratumoral heterogeneity is a theme long believed to be specific for human tumors that arise through many steps driven by accidental lesions occurring at relatively high incidence as a result of DNA damage and chromosome instability. Interestingly, even in highly defined mouse models, where essential driver lesions are introduced by genetic engineering rather than inflicted by damage, there is substantial tumor heterogeneity (Ireland et al 2020). The resulting intratumoral heterogeneity, which is likely to be driven by epigenetic changes in mouse models, is reminiscent of mechanisms that control normal tissue architecture with a guiding role for tissue stem cells.…”

Section: Intratumoral Heterogeneitymentioning

confidence: 99%

Cells of origin of lung cancers: lessons from mouse studies

et al. 2020

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As one of the most common forms of cancer, lung cancers present as a collection of different histological subtypes. These subtypes are characterized by distinct sets of driver mutations and phenotypic appearance, and they often show varying degrees of heterogenicity, aggressiveness, and response/resistance to therapy. Intriguingly, lung cancers are also capable of showing features of multiple subtypes or converting from one subtype to another. The intertumoral and intratumoral heterogeneity of lung cancers as well as incidences of subtype transdifferentiation raise the question of to what extent the tumor characteristics are dictated by the cell of origin rather than the acquired driver lesions. We provide here an overview of the studies in experimental mouse models that try to address this question. These studies convincingly show that both the cell of origin and the genetic driver lesions play a critical role in shaping the phenotypes of lung tumors. However, they also illustrate that there is far from a direct one-to-one relationship between the cell of origin and the cancer subtype, as most epithelial cells can be reprogrammed toward diverse lung cancer fates when exposed to the appropriate set of driver mutations.

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MYC Drives Temporal Evolution of Small Cell Lung Cancer Subtypes by Reprogramming Neuroendocrine Fate

Cited by 340 publications

References 82 publications

SCLC-CellMiner: A Resource for Small Cell Lung Cancer Cell Line Genomics and Pharmacology Based on Genomic Signatures

SCLC-CellMiner: A Resource for Small Cell Lung Cancer Cell Line Genomics and Pharmacology Based on Genomic Signatures

Relationship Between Neuroendocrine and Immune Gene Expression in Small Cell Lung Cancer

Cells of origin of lung cancers: lessons from mouse studies

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