Extracellular signal-regulated kinase mediates chromatin rewiring and lineage transformation in lung cancer
- British Columbia Cancer Agency, Canada
- University of Calgary, Canada
- Memorial Sloan-Kettering Cancer Center, United States
Abstract
Lineage transformation between lung cancer subtypes is a poorly understood phenomenon associated with resistance to treatment and poor patient outcomes. Here, we aimed to model this transition to define underlying biological mechanisms and identify potential avenues for therapeutic intervention. Small cell lung cancer (SCLC) is neuroendocrine in identity and, in contrast to non-SCLC (NSCLC), rarely contains mutations that drive the MAPK pathway. Likewise, NSCLCs that transform to SCLC concomitantly with development of therapy resistance downregulate MAPK signaling, suggesting an inverse relationship between pathway activation and lineage state. To test this, we activated MAPK in SCLC through conditional expression of mutant KRAS or EGFR, which revealed suppression of the neuroendocrine differentiation program via ERK. We found that ERK induces the expression of ETS factors that mediate transformation into a NSCLC-like state. ATAC-seq demonstrated ERK-driven changes in chromatin accessibility at putative regulatory regions and global chromatin rewiring at neuroendocrine and ETS transcriptional targets. Further, ERK-mediated induction of ETS factors as well as suppression of neuroendocrine differentiation were dependent on histone acetyltransferase activities of CBP/p300. Overall, we describe how the ERK-CBP/p300-ETS axis promotes a lineage shift between neuroendocrine and non-neuroendocrine lung cancer phenotypes and provide rationale for the disruption of this program during transformation-driven resistance to targeted therapy.
Data availability
Gene expression data has been deposited to GEO under the accession code GSE160482. ATAC seq data has been deposited to GEO under the accession code GSE160204
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ATAC-seq of lung cancer cell lines with doxycycline KRAS G12V and drug treatmentsNCBI Gene Expression Omnibus, GSE160204.
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Response of SCLC to mutant KRAS or EGFR inductionNCBI Gene Expression Omnibus, GSE160482.
Article and author information
Author details
William W Lockwood
Funding
Canadian Institutes of Health Research (PJT-148725)
- William W Lockwood
Michael Smith Foundation for Health Research (Scholar Award)
- William W Lockwood
Canadian Institutes of Health Research (New Investigator Award)
- William W Lockwood
British Columbia Lung Association (Research Grant)
- Yusuke Inoue
- William W Lockwood
Terry Fox Research Institute (New Investigator Award)
- William W Lockwood
Canadian Institutes of Health Research (PJT-156278)
- Marco Gallo
Canada Research Chairs (Brain Cancer Epigenomics (Tier 2))
- Marco Gallo
Alberta Health Services (Clinician Investigator Program fellowship)
- Ana Nikolic
Alberta Innovates (Fellowship)
- Ana Nikolic
Japanese Respiratory Society (Lilly Oncology Fellowship Program Award)
- Yusuke Inoue
Michael Smith Foundation for Health Research (Fellowship)
- Yusuke Inoue
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Inoue et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Extracellular signal-regulated kinase mediates chromatin rewiring and lineage transformation in lung cancer
eLife 10:e66524.
https://doi.org/10.7554/eLife.66524
Further reading
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Background:
Cervical adenocarcinoma (ADC) is more aggressive compared to other types of cervical cancer (CC), such as squamous cell carcinoma (SCC). The tumor immune microenvironment (TIME) and tumor heterogeneity are recognized as pivotal factors in cancer progression and therapy. However, the disparities in TIME and heterogeneity between ADC and SCC are poorly understood.
Methods:
We performed single-cell RNA sequencing on 11 samples of ADC tumor tissues, with other 4 SCC samples served as controls. The immunochemistry and multiplexed immunofluorescence were conducted to validate our findings.
Results:
Compared to SCC, ADC exhibited unique enrichments in several sub-clusters of epithelial cells with elevated stemness and hyper-malignant features, including the Epi_10_CYSTM1 cluster. ADC displayed a highly immunosuppressive environment characterized by the enrichment of regulatory T cells (Tregs) and tumor-promoting neutrophils. The Epi_10_CYSTM1 cluster recruits Tregs via ALCAM-CD6 signaling, while Tregs reciprocally induce stemness in the Epi_10_CYSTM1 cluster through TGFβ signaling. Importantly, our study revealed that the Epi_10_CYSTM1 cluster could serve as a valuable predictor of lymph node metastasis for CC patients.
Conclusions:
This study highlights the significance of ADC-specific cell clusters in establishing a highly immunosuppressive microenvironment, ultimately contributing to the heightened aggressiveness and poorer prognosis of ADC compared to SCC.
Funding:
Funded by the National Natural Science Foundation of China (82002753; 82072882; 81500475) and the Natural Science Foundation of Hunan Province (2021JJ40324; 2022JJ70103).
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