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Series GSE45162 Query DataSets for GSE45162
Status Public on Jun 22, 2015
Title Mutational activation of a mechanosensitive megachannel drives metastatic cell survival.
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Next-generation sequencing has revolutionized cancer biology by accelerating the unbiased discovery of novel mutations across human cancers. Transforming such discoveries into a conceptual framework of cancer progression requires narrowing the vast number of mutations down to the driver elements, and further reducing these to mutations that govern cancer progression as opposed to tumor initiation. By integrating next-generation RNA-sequencing (RNA-seq) with in vivo selection, we devise an approach that identifies a series of novel recurrent non-synonymous amino acid mutations that are enriched in metastatic breast cancer cells and predicted to significantly alter protein function. These mutations, found in PANX1, RBFA, REST, KRIT1 and ZSWIM6, are detected at higher frequencies in the transcriptomes of two patients’ highly metastatic sub-lines relative to their poorly metastatic parental lines. We functionally characterize the cellular and molecular roles of one of these mutations—a nonsense alteration that yields a truncated pannexin-1 (PANX11-89) plasma membrane megachannel subunit—in metastatic progression. PANX11-89 interacts with full-length PANX1 and augments PANX1 channel activity to promote the survival of cancer cells as they are mechanically deformed. Protection from deformation-induced cell death requires PANX1 channels to release ATP, which acts as a cell autonomous survival signal during mechanical stress. Functional characterization of additional nonsense and missense PANX1 mutations detected in epithelial cancers of the colon, lung, and prostate reveals that these mutants also enhance PANX1-mediated ATP release. In vivo testing of one such truncating mutation detected in a metastatic colorectal tumor also enhances early survival, dissemination and liver metastatic colonization by human colon cancer cells. Finally, pharmacological inhibition of PANX1 inhibits breast cancer metastasis, implicating PANX1 as a novel therapeutic target in cancer. Our findings reveal that ATP release through mechanosensitive PANX1 channels enables cancer cells to overcome a major metastasis suppressive barrier—deformation-induced death in the microvasculature.
Overall design To systematically identify base-pair mutations present in metastatic cells that may drive cancer progression, we performed whole-transcriptome RNA-sequencing (RNA-seq) of in vivo-selected, highly metastatic human breast cancer cell sub-lines, CN-LM1A and MDA-LM2, as well as the CN34 and MDA-MB-231 parental lines from which they were derived. To minimize the false positive rate and allow for subsequent statistical analysis, we sequenced biological replicates of each cell line. Mutations conferring enhanced metastatic capacity should be enriched in the transcriptomes of highly metastatic cells relative to their less metastatic parental populations.
Contributor(s) Furlow PW, Soong D, Zhang S, Halberg N, Mangrum C, Elemento O, Tavazoie SF
Citation(s) 26098574
Submission date Mar 14, 2013
Last update date May 15, 2019
Contact name David Soong
Organization name Weill Cornell Medical College
Department Institute for Computational Biomedicine
Street address 1305 York Avenue
City New York
State/province NY
ZIP/Postal code 10021
Country USA
Platforms (1)
GPL10999 Illumina Genome Analyzer IIx (Homo sapiens)
Samples (8)
GSM1098414 MDA parental cell line rep1
GSM1098415 MDA parental cell line rep2
GSM1098416 MDA LM2 cell line rep1
BioProject PRJNA193090
SRA SRP019275

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Supplementary file Size Download File type/resource
GSE45162_SNV_tables.xlsx.gz 62.7 Mb (ftp)(http) XLSX
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