Hypoxia-mediated translational activation of ITGB3 in breast cancer cells enhances TGF-β signalling and malignant features in vitro and in vivo
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA412005 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6068880_1.fastq.gz | Fastqsanger.gz | |||
| SRR6068880_2.fastq.gz | Fastqsanger.gz | |||
| SRR6068890_1.fastq.gz | Fastqsanger.gz | |||
| SRR6068890_2.fastq.gz | Fastqsanger.gz | |||
| SRR6068900_1.fastq.gz | Fastqsanger.gz |
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Project description:We performed a polysomal RNA-Seq screen in non-malignant breast epithelial (MCF10A) and TNBC (MDA-MB-231) cells exposed to normoxic or hypoxic conditions and/or treated with an mTOR pathway inhibitor. Analysis of both the transcriptome and the translatome identified mRNA transcripts translationally activated or repressed by hypoxia in an mTOR-dependent or -independent manner. The mRNA populations of each sample were converted to cDNA libraries using the TruSeq protocol and then sequenced using a HiSeq 2000 machine. Paired-end reads were mapped against the reference human genome (GRCh38) with STAR v2.5.1b (ENCODE parameters for long RNA) and GENCODE v24 annotation. Gene quantification was performed using RSEM v1.2.28 with default parameters. Only protein-coding genes were included in the analysis. Normalization of the count matrix was performed with the TMM method of the edgeR R package. Polysomal RNA (P) and RNA total (T) fold changes across conditions were calculated with edgeR. Significant genes (FDR < 5% for MCF10A cells and FDR < 10% for MDA-MB-231 cells) in polysomes were selected for translational efficiency calculation (log2FC RNA polysomes/log2FC RNA total). Genes with a z-score > 1.5 were considered to have an increased translational efficiency and genes with a z-score < –1.5 were considered to have a decreased translational efficiency. GO enrichment analysis of significant genes was performed with the DAVID database.
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Project description:The degree and dynamics of translational control during mammalian development remain poorly understood. Here we monitored translation of the mammalian genome as cells become specified and organize into tissues in vivo. This identified unexpected and pervasive translational regulation of most of the core signalling circuitry including Shh,Wnt, Hippo, PI3K and MAPK pathways. We further identify and functionally characterize a complex landscape of upstream open reading frames (uORFs) across 5'-untranslated regions (UTRs) of key signalling components. Focusing on the Shh pathway, we demonstrate the importance of uORFs within the major SHH receptor, Ptch1, in control of cell signalling and neuronal differentiation. Finally, we show that the expression of hundreds of mRNAs underlying critical tissue-specific developmental processes is largely regulated at the translation but not transcript levels. Altogether, this work reveals a new layer of translational control to major signalling components and gene regulatory networks that diversifies gene expression spatially across developing tissues.
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Project description:Breast cancer is the most prevalent malignancy in women and there is an urgent need for new therapeutic drugs targeting aggressive and metastatic subtypes, such as hormone-refractory triple-negative breast cancer (TNBC). Control of protein synthesis is vital to cell growth and tumour progression and permits increased resistance to therapy and cellular stress. Hypoxic cancer cells attain invasive and metastatic properties and chemotherapy resistance, but the regulation and role of protein synthesis in this setting is poorly understood. We performed a polysomal RNA-Seq screen in non-malignant breast epithelial (MCF10A) and TNBC (MDA-MB-231) cells exposed to normoxic or hypoxic conditions and/or treated with an mTOR pathway inhibitor. Analysis of both the transcriptome and the translatome identified mRNA transcripts translationally activated or repressed by hypoxia in an mTOR-dependent or -independent manner. Integrin beta 3 (ITGB3) was translationally activated in hypoxia and its knockdown increased apoptosis and reduced survival and migration, particularly under hypoxic conditions. Moreover, ITGB3 was required for sustained TGF-β pathway activation and for the induction of Snail and associated epithelial-mesenchymal transition markers. ITGB3 downregulation significantly reduced lung metastasis and improved overall survival in mice. Collectively, these data suggest that ITGB3 is translationally activated in hypoxia and regulates malignant features, including epithelial-mesenchymal transition and cell migration, through the TGF-β pathway, revealing a novel angle for the treatment of therapy-resistant hypoxic tumours.
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Project description:Cellière2011 - Plasticity of TGF-β Signalling
Transforming growth factor beta (TGF-β) signalling has been implicated as an important regulator of almost all major cell behaviours, including proliferation, differentiation, cell death, and motility. It remains unclear that how the TGF-β signalling pathway accomplishes the flexibility in its responses. What and how many parameters have to be altered for cells to respond differently to perform complex tasks? This canonical response has been explored in this model, by considering the core signalling architecture of TGF-β pathway.
This model is described in the article:
Plasticity of TGF-β signaling
Cellière G, Fengos G, Hervé M, Iber D.
BMC Syst Biol. 2011 Nov 3;5:184.
Abstract:
The family of TGF-β ligands is large and its members are involved in many different signaling processes. These signaling processes strongly differ in type with TGF-β ligands eliciting both sustained or transient responses. Members of the TGF-β family can also act as morphogen and cellular responses would then be expected to provide a direct read-out of the extracellular ligand concentration. A number of different models have been proposed to reconcile these different behaviours. We were interested to define the set of minimal modifications that are required to change the type of signal processing in the TGF-β signaling network.
RESULTS:
To define the key aspects for signaling plasticity we focused on the core of the TGF-β signaling network. With the help of a parameter screen we identified ranges of kinetic parameters and protein concentrations that give rise to transient, sustained, or oscillatory responses to constant stimuli, as well as those parameter ranges that enable a proportional response to time-varying ligand concentrations (as expected in the read-out of morphogens). A combination of a strong negative feedback and fast shuttling to the nucleus biases signaling to a transient rather than a sustained response, while oscillations were obtained if ligand binding to the receptor is weak and the turn-over of the I-Smad is fast. A proportional read-out required inefficient receptor activation in addition to a low affinity of receptor-ligand binding. We find that targeted modification of single parameters suffices to alter the response type. The intensity of a constant signal (i.e. the ligand concentration), on the other hand, affected only the strength but not the type of the response.
CONCLUSIONS:
The architecture of the TGF-β pathway enables the observed signaling plasticity. The observed range of signaling outputs to TGF-β ligand in different cell types and under different conditions can be explained with differences in cellular protein concentrations and with changes in effective rate constants due to cross-talk with other signaling pathways. It will be interesting to uncover the exact cellular differences as well as the details of the cross-talks in future work.
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