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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.
Pubmed ID: 34121659
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Software tool for versatile matrix visualization and analysis. Program to generate heatmaps from input data. JavaScript matrix visualization and analysis.
View all literature mentionsNon-profit plasmid repository dedicated to helping scientists around the world share high-quality plasmids. Facilitates archiving and distributing DNA-based research reagents and associated data to scientists worldwide. Repository contains over 65,000 plasmids, including special collections on CRISPR, fluorescent proteins, and ready-to-use viral preparations. There is no cost for scientists to deposit plasmids, which saves time and money associated with shipping plasmids themselves. All plasmids are fully sequenced for validation and sequencing data is openly available. We handle the appropriate Material Transfer Agreements (MTA) with institutions, facilitating open exchange and offering intellectual property and liability protection for depositing scientists. Furthermore, we curate free educational resources for the scientific community including a blog, eBooks, video protocols, and detailed molecular biology resources.
View all literature mentionsOriginal SAMTOOLS package has been split into three separate repositories including Samtools, BCFtools and HTSlib. Samtools for manipulating next generation sequencing data used for reading, writing, editing, indexing,viewing nucleotide alignments in SAM,BAM,CRAM format. BCFtools used for reading, writing BCF2,VCF, gVCF files and calling, filtering, summarising SNP and short indel sequence variants. HTSlib used for reading, writing high throughput sequencing data.
View all literature mentionsSoftware package for interpreting gene expression data. Used for interpretation of a large-scale experiment by identifying pathways and processes.
View all literature mentionsData analysis service for gene-list enrichment analysis against a manual database. It allows users to input lists of mammalian gene symbols for which the program computes over-representation of transcription factor targets from the ChIP-X database. The database integrates interaction data from ChIP-chip, ChIP-seq, ChIP-PET and DamID studies and contains 189,933 interactions, manually extracted from 87 publications, describing the binding of 92 transcription factors to 31,932 target genes.
View all literature mentionsAn Antibody supplier who also provides assay services and products.
View all literature mentionsJava toolset for working with next generation sequencing data in the BAM format.
View all literature mentionsA powerful toolset for genome arithmetic allowing one to address common genomics tasks such as finding feature overlaps and computing coverage. Bedtools allows one to intersect, merge, count, complement, and shuffle genomic intervals from multiple files in widely-used genomic file formats such as BAM, BED, GFF/GTF, VCF. While each individual tool is designed to do a relatively simple task (e.g., intersect two interval files), quite sophisticated analyses can be conducted by combining multiple bedtools operations on the UNIX command line.
View all literature mentionsEncyclopedia of DNA elements consisting of list of functional elements in human genome, including elements that act at protein and RNA levels, and regulatory elements that control cells and circumstances in which gene is active. Enables scientific and medical communities to interpret role of human genome in biology and disease. Provides identification of common cell types to facilitate integrative analysis and new experimental technologies based on high-throughput sequencing. Genome Browser containing ENCODE and Epigenomics Roadmap data. Data are available for entire human genome.
View all literature mentionsSoftware tools for Motif Discovery and next-gen sequencing analysis. Used for analyzing ChIP-Seq, GRO-Seq, RNA-Seq, DNase-Seq, Hi-C and numerous other types of functional genomics sequencing data sets. Collection of command line programs for unix style operating systems written in Perl and C++.
View all literature mentionsSoftware package for the analysis of gene expression microarray data, especially the use of linear models for analyzing designed experiments and the assessment of differential expression.
View all literature mentionsModeling and simulation environment for study of multi scale and multicellular systems. Users can construct and simulate models of gene regulation, signaling pathways, tissue patterning and morphogenesis and explore the effects of multiscale feedbacks between these processes. Morpheus can render 2D and 3D models using graphical user interface.
View all literature mentionsSoftware package for differential gene expression analysis based on the negative binomial distribution. Used for analyzing RNA-seq data for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates.
View all literature mentionsCell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H2347 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H524 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H358 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H526 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HCC2935 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HCC2279 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HCC4006 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H82 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H2107 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H460 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H1395 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HCC4011 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line A-549 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H1792 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H1650 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H1155 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H23 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HCC827 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H1975 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentions