MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment

Wilson, Rae Anna; Espinosa‐Díez, Cristina; Kanner, Nathan; Chatterjee, Namita; Ruhl, Rebecca; Subbiah, Ramesh; Advani, Sunil J.; Li, Jie; Khan, Omar F.; Franovic, Aleksandra; Weis, Sara M.; Kumar, Sushil; Coussens, Lisa M.; Anderson, Daniel G.; Chen, Clark C.; Cheresh, David A.; Anand, Sudarshan

doi:10.1038/ncomms13597

Cited by 54 publications

(52 citation statements)

References 43 publications

(45 reference statements)

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“…An optimal dose range is likely to exist, below which immune stimulation might be suboptimal and above which immunosuppression prevails 44 . Seminal studies using breast cancer models showed that the DNA exonuclease 3 repair exonuclease 1 (TREX1) inhibits immune activation 45,46 . TREX1 is induced by radiation doses above 12–18 Gy in different colorectal carcinoma and breast cancer cell lines, and it attenuates immunogenicity by degrading double-strand DNA that accumulates in the cytosol upon radiation 47 .…”

Section: Boosting the Abscopal Effectmentioning

confidence: 99%

Using immunotherapy to boost the abscopal effect

et al. 2018

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More than 60 years ago, the effect whereby radiotherapy at one site may lead to regression of metastatic cancer at distant sites that are not irradiated was described and called the abscopal effect (from ‘ab scopus’, that is, away from the target). The abscopal effect has been connected to mechanisms involving the immune system. However, the effect is rare because at the time of treatment, established immune-tolerance mechanisms may hamper the development of sufficiently robust abscopal responses. Today, the growing consensus is that combining radiotherapy with immunotherapy provides an opportunity to boost abscopal response rates, extending the use of radiotherapy to treatment of both local and metastatic disease. In this Opinion article, we review evidence for this growing consensus and highlight emerging limitations to boosting the abscopal effect using immunotherapy. This is followed by a perspective on current and potential cross-disciplinary approaches, including the use of smart materials to address these limitations.

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Section: Boosting the Abscopal Effectmentioning

confidence: 99%

Using immunotherapy to boost the abscopal effect

et al. 2018

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“…We and others have shown that radiation regulated miRs alter DNA damage repair pathways, pro-survival signaling pathways, cell-cycle checkpoint regulation, and apoptosis; functions which radiation therapy exploits for therapeutic gain (19)(20)(21)(22)(23)(24). Our previous work identified a group of miRs regulated in the tumor vasculature in response to radiation (25). In particular, we have observed that some miRs in ECs are differentially regulated in response to different doses of radiation.…”

Section: Introductionmentioning

confidence: 85%

Differential regulation of microRNA-15a by radiation affects angiogenesis and tumor growth via modulation of acid sphingomyelinase

Rana¹,

Espinosa‐Díez²,

Ruhl³

et al. 2018

Preprint

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Activation of acid sphingomyelinase (SMPD1) and the generation of ceramide is a critical regulator of apoptosis in response to cellular stress including radiation. Endothelial SMPD1 has been shown to regulate tumor responses to radiation therapy. We show here that the SMPD1 gene is regulated by a microRNA (miR), miR-15a, in endothelial cells (ECs). Standard low dose radiation (2 Gy) upregulates miR-15a and decreases SMPD1 levels. In contrast, high dose radiation (10 Gy and above) decreases miR-15a and increases SMPD1. Ectopic expression of miR-15a decreases both mRNA and protein levels of SMPD1. Mimicking the effects of high dose radiation with a miR-15a inhibitor decreases cell proliferation and increases active Caspase-3 & 7. Mechanistically, inhibition of miR-15a increases inflammatory cytokines, such as IP10, activates caspase-1 inflammasome and increases Gasdermin D, an effector of pyroptosis. Importantly, both systemic and vascular-targeted delivery of miR-15a inhibitor decreases angiogenesis and tumor growth in a CT26 murine colorectal carcinoma model. Taken together, our findings highlight a novel role for miR mediated regulation of SMPD1 during radiation responses and establish proof-of-concept that this pathway can be targeted with a miR inhibitor.

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“…We have previously described how acute genotoxic stress stimulus lead to apoptosis and high doses of IR lead to EC cell death [2]. As MEG9 function in adult EC has not been described in depth, we tested if it has a role in triggering cell death.…”

Section: Meg9 Loss Of Function Leads To Increase Apoptosis and Decreamentioning

confidence: 99%

“…Depending on how severe the damage is, endothelial cells (ECs) make quick decisions among cell death, cell cycle arrest or survival. We have demonstrated how the expression of specific group of miRs can influence endothelial fate [1,2] in the context of DNA damage responses. However, the role of long non-coding RNAs (lncRNAs) in the endothelial stress responses is unclear.…”

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confidence: 99%

DNA damage dependent hypomethylation regulates the pro-angiogenic LncRNA MEG9

Espinosa‐Díez¹,

Wilson²,

Mukherjee³

et al. 2018

Preprint

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Changes in gene expression are key for the cells to adapt and response to intrinsic and extrinsic stimulus. It has been shown that genotoxic stress induces global hypomethylation as a result of decreased expression of DNA methyl transferases (DNMT). We hypothesized that DNA damage suppresses long non-coding RNA expression in the vasculature via DNA methylation leading to more robust DNA repair/survival or cellular senescence/death cell fate decisions. We show here that ionizing radiation reduces the expression of DNMTs in the vascular endothelium and this leads to increased expression of the anti-apoptotic lncRNA MEG9. MEG9 is a lncRNA from the DLK1-DIO3 ncRNA cluster. Loss-of-function studies using RNA gapmers indicate that MEG9 protects endothelial cells from DNA damage induced cell death. Consistent with this phenotype, knockdown of MEG9 decreases growth factor dependent angiogenesis in a 3D fibrin gel angiogenesis assay. Mechanistically, we observed that MEG9 knockdown decreased the expression of cell survival genes including survivin and induced the expression of pro-apoptotic genes such as Bad/Bax. Taken together, our findings illustrate how DNA methylation at selective lncRNA loci can regulate their expression and drive endothelial cell fate decisions.

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MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment

Cited by 54 publications

References 43 publications

Using immunotherapy to boost the abscopal effect

Using immunotherapy to boost the abscopal effect

Differential regulation of microRNA-15a by radiation affects angiogenesis and tumor growth via modulation of acid sphingomyelinase

DNA damage dependent hypomethylation regulates the pro-angiogenic LncRNA MEG9

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