Mitochondrial fusion limits breast cancer metastasis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1027379 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26371238.fastq.gz | Fastqsanger.gz | |||
| SRR26371239.fastq.gz | Fastqsanger.gz | |||
| SRR26371240.fastq.gz | Fastqsanger.gz | |||
| SRR26371241.fastq.gz | Fastqsanger.gz | |||
| SRR26371242.fastq.gz | Fastqsanger.gz |
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Project description:Mitochondrial metabolism plays a central role in promoting cancer growth and metastatic progression. The transition between a hyperfused and fragmented mitochondrial network is termed mitochondrial dynamics and is important for many mitochondria-associated functions; however, little is known regarding how this process influences metastasis. Here, we show that breast cancer cells with low metastatic potential exhibit a more fused mitochondrial network compared to highly metastatic breast cancer cells. To examine whether a fused mitochondrial network could impair metastasis, we inhibited mitochondrial fission in metastatic breast cancer cells by individual genetic deletion of three key regulators of mitochondrial fission (Drp1, Fis1 and Mff) or pharmacological intervention using leflunomide, an anti-rheumatic drug. These cells displayed a fused mitochondrial network and limited survival under anoikis conditions, consistent with mitochondrial fusion limiting metastasis. Transcriptomics and metabolomics analyses revealed that mitochondrial fusion causes significant alterations in metabolic pathways and processes related to cell adhesion. Functional bioenergetics assays demonstrated that mitochondrial fusion limited the mitochondrial capacity of cancer cells. Mitochondrial fusion in breast cancer cells had no significant effect on primary tumor growth but almost completely ablated lung metastasis in vivo. Furthermore, the transcriptomics signature associated with enhanced mitochondrial fusion correlated with improved survival in patients with breast cancer. Overall, our findings highlight mitochondrial fusion as a therapeutic opportunity for breast cancer.
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Project description:In several developmental lineages, an increase in expression of the MYC proto-oncogene drives the transition from quiescent stem cells to transit amplifying cells. The mechanism by which MYC restricts self-renewal of adult stem cells is unknown. Here, we show that MYC activates a stereotypic transcriptional program of genes involved in protein translation and mitochondrial biogenesis in mammary epithelial cells and indirectly inhibits the YAP/TAZ co-activators that are essential for mammary stem cell self-renewal. We identify a phospholipase of the mitochondrial outer membrane, PLD6, as the mediator of MYC activity. PLD6 mediates a change in the mitochondrial fusion/fission balance that promotes nuclear export of YAP/TAZ in a LATS- and RHO-independent manner. Mouse models and human pathological data confirm that MYC suppresses YAP/TAZ activity in mammary tumors. PLD6 is also required for glutaminolysis, arguing that MYC-dependent changes in mitochondrial dynamics balance cellular energy metabolism with the self-renewal potential of adult stem cells. ChIP-Seq experiments for MYC-HA (HA-IP) performed in IMEC primary breast epithelial cells. Input-samples were sequenced as controlls.
2015-10-28 | E-GEOD-66252 | biostudies-arrayexpress
Project description:Although it is reported that mitochondria-localized nuclear transcription factors (TFs) regulate mitochondrial processes such as apoptosis and mitochondrial transcription/respiration, their functions and mechanisms of mitochondrial dynamics regulated by mitochondria-localized nuclear TFs are yet to be fully characterized. Here, we identify STAT6 as a mitochondrial protein that is localized in the outer membrane of mitochondria (OMM). In addition to regulating mitochondrial gene expression as a nuclear TF, STAT6 in OMM inhibits mitochondrial fusion by blocking MFN2 dimerization. This implies that STAT6 has dual role in overall mitochondrial process. Moreover, mitochondrial accumulation of STAT6 in response to these findings reveal that STAT6 is a new regulator of mitochondrial processes including mitochondrial biogenesis and fusion/fission mechanisms.
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Project description:Mitochondrial metabolism recently emerged as a critical dependency in acute myeloid leukemia (AML). The shape of mitochondria is tightly regulated by dynamin GTPase proteins, which drive opposing fusion and fission forces to consistently adapt bioenergetics to the cellular context. Here, we showed that targeting mitochondrial structure through the inhibition of mitochondrial fusion was a new vulnerability of AML cells, when assayed in patient-derived xenograft (PDX) models. Genetic depletion of mitofusin 2 (MFN2) or optic atrophy 1 (OPA1) or pharmacological inhibition of OPA1 (MYLS22) blocked mitochondrial fusion and had significant anti-leukemic activity, while having limited impact on normal hematopoietic cells ex vivo and in vivo. Mechanistically, inhibition of mitochondrial fusion disrupted mitochondrial respiration and reactive oxygen species production, leading to cell cycle arrest at the G0/G1 transition. These results nominate the inhibition of mitochondrial fusion as a promising therapeutic approach for AML.
2023-03-16 | GSE222168 | GEO
Project description:Mitochondrial metabolism recently emerged as a critical dependency in acute myeloid leukemia (AML). The shape of mitochondria is tightly regulated by dynamin GTPase proteins, which drive opposing fusion and fission forces to consistently adapt bioenergetics to the cellular context. Here, we showed that targeting mitochondrial structure through the inhibition of mitochondrial fusion was a new vulnerability of AML cells, when assayed in patient-derived xenograft (PDX) models. Genetic depletion of mitofusin 2 (MFN2) or optic atrophy 1 (OPA1) or pharmacological inhibition of OPA1 (MYLS22) blocked mitochondrial fusion and had significant anti-leukemic activity, while having limited impact on normal hematopoietic cells ex vivo and in vivo. Mechanistically, inhibition of mitochondrial fusion disrupted mitochondrial respiration and reactive oxygen species production, leading to cell cycle arrest at the G0/G1 transition. These results nominate the inhibition of mitochondrial fusion as a promising therapeutic approach for AML.
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Project description:In several developmental lineages, an increase in expression of the MYC proto-oncogene drives the transition from quiescent stem cells to transit amplifying cells. The mechanism by which MYC restricts self-renewal of adult stem cells is unknown. Here, we show that MYC activates a stereotypic transcriptional program of genes involved in protein translation and mitochondrial biogenesis in mammary epithelial cells and indirectly inhibits the YAP/TAZ co-activators that are essential for mammary stem cell self-renewal. We identify a phospholipase of the mitochondrial outer membrane, PLD6, as the mediator of MYC activity. PLD6 mediates a change in the mitochondrial fusion/fission balance that promotes nuclear export of YAP/TAZ in a LATS- and RHO-independent manner. Mouse models and human pathological data confirm that MYC suppresses YAP/TAZ activity in mammary tumors. PLD6 is also required for glutaminolysis, arguing that MYC-dependent changes in mitochondrial dynamics balance cellular energy metabolism with the self-renewal potential of adult stem cells. RNA-Seq Experiments in 2 different primary breast epithelial cell lines (HMLE, which were sorted according to CD44/CD24 surface markers & unsorted IMEC). Both cell lines expressed a doxycycline-inducible version of MYC. For the HMLE cell line DGE analysis was performed for the uninduced (EtOH) situation, comparing CD44high vs CD44 low and for the induced situation Dox vs. EtOH for the CD44high population. For the IMEC cell line DGE was performed by comparing Dox-treated populations expressing either Dox-inducible MYC or a vector control which allows to filter out potential effects due to doxycycline treatment.
2015-10-28 | E-GEOD-66250 | biostudies-arrayexpress