An ARF6–Exportin-5 axis delivers pre-miRNA cargo to tumour microvesicles

Clancy, James; Zhang, Ye; Sheehan, Colin; D’Souza‐Schorey, Crislyn

doi:10.1038/s41556-019-0345-y

Cited by 111 publications

(108 citation statements)

References 69 publications

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“…The exosome is a disk-shaped membranous vesicle with a diameter 30-100 nm, and carries a parental cell cargo including lipids, metabolites, proteins, nucleic acids (DNA fragments, mRNA, miRNA, etc.) delivers pre-miRNA cargo into tumor microvesicles [26]. These regulatory methods demonstrate the mechanism by which ovarian cancer exosomes obtain their distinct molecular signature from surrounding healthy tissue.…”

Section: Exosome Biogenesismentioning

confidence: 95%

Exosomes promote pre-metastatic niche formation in ovarian cancer

et al. 2019

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Ovarian cancer is one of the most common gynecological malignancies. Upon initial diagnosis, the majority of patients present with widespread metastatic growth within the peritoneal cavity. This metastatic growth occurs in stages, with the formation of a pre-metastatic niche occurring prior to macroscopic tumor cell invasion. Exosomes released by the primary ovarian tumor are small extracellular vesicles which prepare the distant tumor microenvironment for accelerated metastatic invasion. They regulate intercellular communication between tumor cells and normal stroma, cancer-associated fibroblasts, and local immune cells within the tumor microenvironment. In this review, we highlight the emerging roles of ovarian cancer exosomes as coordinators of pre-metastatic niche formation, biomarkers amenable to liquid biopsy, and targets of chemotherapy.Ovarian cancer is the deadliest gynecological malignancy, largely stemming from peritoneal metastasis. Formation of the pre-metastatic niche supports subsequent metastatic lesions. Ovarian cancer derived exosomes induce premetastatic niche formation via immunosuppression, angiogenesis, stromal cell remodeling, and oncogenic reprogramming. Ovarian cancer derived exosomes are promising biomarkers and therapeutic targets.

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Section: Exosome Biogenesismentioning

confidence: 95%

Exosomes promote pre-metastatic niche formation in ovarian cancer

et al. 2019

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“…There is mounting evidence that exosomes mediate the transfer of mRNAs and microRNAs between cells . Recently, it has been reported that PTEN suppression in brain metastatic tumor cells is epigenetically regulated by microRNAs delivered by astrocyte‐derived exosome promoting intercellular transfer of PTEN‐targeting microRNAs to metastatic tumor cells . Caprin‐1 has been associated with the formation of RNA granules and serves as a regulator of post‐transcriptional and epigenetic expression .…”

Section: Resultsmentioning

confidence: 99%

Caprin‐1 Promotes Cellular Uptake of Nucleic Acids with Backbone and Sequence Discrimination

Galli

Sadhu

Masi

et al. 2019

Helvetica Chimica Acta

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The cellular delivery of oligonucleotides has been a major obstacle in the development of therapeutic antisense agents. PNAs (Peptide Nucleic Acid) are unique in providing a modular peptidic backbone that is amenable to structural and charge modulation. While cationic PNAs have been shown to be taken up by cells more efficiently than neutral PNAs, the generality of uptake across different nucleobase sequences has never been tested. Herein, we quantified the relative uptake of PNAs across a library of 10 000 sequences for two different PNA backbones (cationic and neutral) and identified sequences with high uptake and low uptake. We used the high uptake sequence as a bait for target identification, leading to the discovery that a protein, caprin-1, binds to PNA with backbone and sequence discrimination. We further showed that purified caprin-1 added to cell cultures enhanced the cellular uptake of PNA as well as DNA and RNA. Figure 2. Single sequence specificity uptake of Ser-PNAs in HeLa cells. A) Maximum projection of Z-stacks images comparing the internalization of Cy3 labelled HU sequence (high uptake sequence) and LU sequence (low uptake sequence) and Arg/Ser peptides. Cell membrane was stained with CellMask Green Plasma Membrane Stain (Thermo Fisher Scientific, Waltham, MA, USA). B) Plots of Cy3 fluorescent signal quantification in cells. Number of cells analyzed: Ser-HU n = 61, Ser-LU n = 68, Arg-HU n = 70, Arg-LU n = 57, Ser-peptide n = 19, Arg-peptide n = 14 (bars are averages � SEM, unpaired t-test, p-values < 0.0001). C) HU and LU nucleobase sequences. The modified residues (either α-arginine modification or γ-serine modification) are shown in red. Scale bar: 10 μm.

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“…The process that leads to MVs generation starts from the formation of outward buds in specific sites of the membrane, followed by fission and subsequent release of the vesicle into the extracellular space [34,35]. This process involves specific machinery in which ADP-ribosylation factor 6 (ARF6) plays a central role [34,36]. They have multiple biological functions depending on the cell type from which they originate and/or on the cargo content that includes proteins and RNAs, including miRNAs [37].…”

Section: Characteristics Of Extracellular Vesiclesmentioning

confidence: 99%

The Crosstalk between Tumor Cells and the Microenvironment in Hepatocellular Carcinoma: The Role of Exosomal microRNAs and Their Clinical Implications

Pascut

Pratama

Võ

et al. 2020

Cancers

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The communication between hepatocellular carcinoma (HCC) cells and their microenvironment is an essential mechanism supporting or preventing tumor development and progression. Recent evidence has identified extracellular vesicles (EVs) as one of the mechanisms mediating paracrine signaling between cells. Exosomes, the most described class of EVs, deliver proteins, mRNAs, noncoding RNAs, DNA, and lipids to recipient cells, also at remote distances. MicroRNAs (miRNAs), as part of the non-coding RNA exosomal cargo, have an important role in regulating cellular pathways in targeted cells, regulating several processes related to tumor progression invasion and metastasis, such as angiogenesis, immune-escape, epithelial-to-mesenchymal transition, invasion, and multi-drug resistance. Accumulating evidence suggests exosomal miRNAs as relevant players in the dynamic crosstalk among cancerous, immune, and stromal cells in establishing the tumorigenic microenvironment. In addition, they sustain the metastasic niche formation at distant sites. In this review, we summarized the recent findings on the role of the exosome-derived miRNAs in the cross-communication between tumor cells and different hepatic resident cells, with a focus on the molecular mechanisms responsible for the cell re-programming. In addition, we describe the clinical implication derived from the exosomal miRNA-driven immunomodulation to the current immunotherapy strategies and the molecular aspects influencing the resistance to therapeutic agents.

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An ARF6–Exportin-5 axis delivers pre-miRNA cargo to tumour microvesicles

Cited by 111 publications

References 69 publications

Exosomes promote pre-metastatic niche formation in ovarian cancer

Exosomes promote pre-metastatic niche formation in ovarian cancer

Caprin‐1 Promotes Cellular Uptake of Nucleic Acids with Backbone and Sequence Discrimination

The Crosstalk between Tumor Cells and the Microenvironment in Hepatocellular Carcinoma: The Role of Exosomal microRNAs and Their Clinical Implications

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