Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1213840 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32068449_1.fastq.gz | Fastqsanger.gz | |||
| SRR32068449_2.fastq.gz | Fastqsanger.gz | |||
| SRR32068450_1.fastq.gz | Fastqsanger.gz | |||
| SRR32068450_2.fastq.gz | Fastqsanger.gz | |||
| SRR32068451_1.fastq.gz | Fastqsanger.gz |
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Project description:Endoplasmic reticulum to mitochondria Ca2+ transfer is important for cancer cell survival, but the role of mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU) in pancreatic adenocarcinoma (PDAC) is poorly understood. Here, we show that increased MCU expression is associated with malignancy and poorer outcomes in PDAC patients. In isogenic murine PDAC models, Mcu deletion (McuKO) ablated mitochondrial Ca2+ uptake, which reduced proliferation and inhibited self-renewal. Orthotopic implantation of MCU-null tumor cells reduced primary tumor growth and metastasis. Mcu deletion reduced the cellular plasticity of tumor cells by inhibiting epithelial-to- mesenchymal transition (EMT), which contributes to metastatic competency in PDAC. Mechanistically, the loss of mitochondrial Ca2+ uptake reduced expression of the key EMT transcription factor Snail and secretion of the EMT-inducing ligand TGFβ. Snail re-expression and TGFβ treatment rescued deficits in McuKO cells and restored their metastatic ability. Thus, MCU may present a therapeutic target in PDAC to limit cancer-cell-induced EMT and metastasis.
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Project description:RNA localization is one mechanism that neurons use to spatially and temporally regulate gene expression at synapses. Here, we tested the hypothesis that cells exhibiting distinct forms of synaptic plasticity will have differences in dendritically localized RNAs. Indeed, we discovered that each major subregion of the adult mouse hippocampus expresses a unique complement of dendritic RNAs. Specifically, we uncovered a surprising number of cell type and compartment specific differences in RNA expression and alternative splicing, some of which pointed to differences within interneuron and non-neuronal cells present in dendritic laminae. Further, by focusing gene-ontology analyses on the plasticity-resistant CA2, we identified an enrichment of mitochondria-associated pathways in CA2 cell bodies and dendrites, and we provide functional evidence that these pathways influence plasticity and mitochondrial respiration in CA2. In sum, our results support accumulating evidence that thousands of RNAs are present in adult dendrites that likely function to regulate cell type specific processes in dendrites.
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Project description:RNA localization is one mechanism that neurons use to spatially and temporally regulate gene expression at synapses. Here, we tested the hypothesis that cells exhibiting distinct forms of synaptic plasticity will have differences in dendritically localized RNAs. Indeed, we discovered that each major subregion of the adult mouse hippocampus expresses a unique complement of dendritic RNAs. Specifically, we uncovered a surprising number of cell type and compartment specific differences in RNA expression and alternative splicing, some of which pointed to differences within interneuron and non-neuronal cells present in dendritic laminae. Further, by focusing gene-ontology analyses on the plasticity-resistant CA2, we identified an enrichment of mitochondria-associated pathways in CA2 cell bodies and dendrites, and we provide functional evidence that these pathways influence plasticity and mitochondrial respiration in CA2. In sum, our results support accumulating evidence that thousands of RNAs are present in adult dendrites that likely function to regulate cell type specific processes in dendrites.
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Project description:Endoplasmic reticulum to mitochondria Ca2+ transfer is important for cancer cell survival, but the role of mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU) in pancreatic adenocarcinoma (PDAC) is poorly understood. Here, we show that increased MCU expression is associated with malignancy and poorer outcomes in PDAC patients. In isogenic murine PDAC models, Mcu deletion (Mcu KO) ablated mitochondrial Ca2+ uptake, which reduced proliferation and inhibited self-renewal. Orthotopic implantation of MCU-null tumor cells reduced primary tumor growth and metastasis. Mcu deletion reduced the cellular plasticity of tumor cells by inhibiting epithelial-to-mesenchymal transition (EMT), which contributes to metastatic competency in PDAC. Mechanistically, the loss of mitochondrial Ca2+ uptake reduced expression of the key EMT transcription factor Snail and secretion of the EMT-inducing ligand TGFβ. Snail re-expression and TGFβ treatment rescued deficits in Mcu KO cells and restored their metastatic ability. Thus, MCU may present a therapeutic target in PDAC to limit cancer-cell-induced EMT and metastasis.
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Project description:Cardiomyocyte Ca2+ is buffered by mitochondria via the mitochondrial calcium uniporter (MCU) complex. The MCU complex consists of pore-forming proteins including the mitochondrial calcium uniporter (MCU), and regulatory proteins such as mitochondrial calcium uptake proteins 1 and 2 (MICU1/2). The stoichiometry of these proteins influences the sensitivity to Ca2+ and activity of the complex. However, the factors that regulate their gene expression remain incompletely understood. Long non-coding RNAs (lncRNAs) regulate gene expression through various mechanisms, and we recently found that the lncRNA Tug1 affected the expression of MCU-associated genes. To further explore this, we knocked down Tug1 (Tug1 KD) in H9c2 rat cardiomyocytes using antisense LNA oligo. This led to increased MCU protein expression yet this did not enhance a marker of mitochondrial Ca2+ uptake. RNA-seq revealed that Tug1 KD increased Mcu and led to differential expression of genes and pathways related to Ca2+ regulation in the heart. To understand the effect of this on Ca2+ signalling, we measured phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and its downstream target cAMP Response Element-Binding protein (CREB), a transcription factor known to promote Mcu gene expression. Tug1 KD attenuated the increase in CAMKII and CREB phosphorylation in response to ionomycin, a Ca2+ ionophore. Inhibition of CaMKII, but not CREB, partially prevented the Tug1 KD mediated increase in Mcu. Together, these data suggest that Tug1 modulates MCU expression via a mechanism that may involve CAMKII and CREB. The Tug1 mediated regulation of MCU on mitochondrial Ca2+ uptake, may have functional consequences for cellular Ca2+ handling which could have implications for cardiac disease.
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