Visualization and tracking of tumour extracellular vesicle delivery and RNA translation using multiplexed reporters

Lai, Charles P.; Kim, Edward Y.; Badr, Christian E.; Weissleder, Ralph; Mempel, Thorsten R.; Tannous, Bakhos A.; Breakefield, Xandra O.

doi:10.1038/ncomms8029

Cited by 474 publications

(529 citation statements)

References 65 publications

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“…6 To confirm that FN is located on the exosome surface as would be expected, we used a dot blot assay that can distinguish EV surface proteins from lumen proteins based on permeabilization of EVs in 0.1% Tween-20. 33,34 The tetraspanin CD63 was used as a positive control, as it is a well-characterized exosomal surface protein. Using an antibody to the large extracellular loop, CD63 was detected in both detergent-free and -containing conditions (Fig.…”

Section: Resultsmentioning

confidence: 99%

Exosome secretion promotes chemotaxis of cancer cells

Sung

Weaver

2017

Cell Adhesion & Migration

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Migration of cells toward chemical cues, or chemotaxis, is important for many biologic processes such as immune defense, wound healing and cancer metastasis. Although chemotaxis is thought to occur in cancer cells, it is less well characterized than chemotaxis of professional immune cells such as neutrophils. Here, we show that cancer cell chemotaxis relies on secretion of exosome-type extracellular vesicles. Migration of fibrosarcoma cells toward a gradient of exosome-depleted serum was diminished by knockdown of the exosome secretion regulator Rab27a. Rescue experiments in which chemotaxis chambers were coated with purified extracellular vesicles demonstrate that exosomes but not microvesicles affect both speed and directionality of migrating cells. Chamber coating with purified fibronectin and fibronectin-depleted exosomes demonstrates that the exosome cargo fibronectin promotes cell speed but cannot account for the role of exosomes in promoting directionality of fibrosarcoma cell movement during chemotaxis. These experiments indicate that exosomes contain multiple motility-promoting cargoes that contribute to different aspects of cell motility.

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Section: Resultsmentioning

confidence: 99%

Exosome secretion promotes chemotaxis of cancer cells

Sung

Weaver

2017

Cell Adhesion & Migration

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“…In tracing the target cells of EVs, transmembrane proteins fused to luciferase or fluorescent proteins in EVs can be used as tracers, and the luciferase or fluorescent activity of distant cells can be measured to trace the effects of EVs 42, 111…”

Section: Modular Design Of Surface Proteinsmentioning

confidence: 99%

“…Lai et al designed a practical tool, EVs containing fluorescently labeled mRNA to confirm the internalization of EVs by measuring the signal 42. Another effective and more proven method utilizes the Cre–LoxP system, in which transgenic mice express the LacZ reporter gene with a STOP sequence, which can be excised by Cre to subsequently exhibit LacZ expression after transfection with EVs containing Cre mRNA 113.…”

Section: Modular Design Of Internal Contentsmentioning

confidence: 99%

“…However, completely natural EVs may not be sufficient to provide treatments for all kinds of disease conditions; modified EVs have therefore been developed, indicating the beginning of the era of modularized EVs. A variety of modified EVs, including EVs specifically enriched in mRNA,42 miRNA,12, 43 and small interfering RNA (siRNA),20, 44 EVs with membrane modification,45, 46 and EVs carrying small molecule drugs47 and superparamagnetic iron oxide nanoparticles48 have been developed. As the era of personalized and precision medicine continues to develop, the demands of both the targeting ability toward pathological organization combined with limited damage to normal tissues49 to minimize side effects (precision medicine) and freely assembled agents based on a patient's personalized database50, 51 to maximize therapeutic effects (personalized medicine) will continually increase.…”

Section: Introductionmentioning

confidence: 99%

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Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

2018

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Extracellular vesicles (EVs) are ubiquitous nanosized membrane vesicles consisting of a lipid bilayer enclosing proteins and nucleic acids, which are active in intercellular communications. EVs are increasingly seen as a vital component of many biological functions that were once considered to require the direct participation of stem cells. Consequently, transplantation of EVs is gradually becoming considered an alternative to stem cell transplantation due to their significant advantages, including their relatively low probability of neoplastic transformation and abnormal differentiation. However, as research has progressed, it is realized that EVs derived from native‐source cells may have various shortcomings, which can be corrected by modification and optimization. To date, attempts are made to modify or improve almost all the components of EVs, including the lipid bilayer, proteins, and nucleic acids, launching a new era of modularized EV therapy through the “modular design” of EV components. One high‐yield technique, generating EV mimetic nanovesicles, will help to make industrial production of modularized EVs a reality. These modularized EVs have highly customized “modular design” components related to biological function and targeted delivery and are proposed as a promising approach to achieve personalized and precision medicine.

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“…More studies addressing this issue are needed that could discover the tumor-specific targeting of these exosomes. Quick biodistribution of exosomes applied systemically and their elimination in 1-6 hours after administration [33][34][35] suggests that AMF exposition should be applied shortly after the magnetoexosome application.…”

mentioning

confidence: 99%

Human mesenchymal stem cell-derived iron oxide exosomes allow targeted ablation of tumor cells via magnetic hyperthermia

Altanerova¹,

Babincová²,

Babinec³

et al. 2017

IJN

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Magnetic hyperthermia, or the heating of tissues using magnetic materials, is a promising approach for treating cancer. We found that human mesenchymal stem cells (MSCs) isolated from various tissues and MSCs expressing the yeast cytosine deaminase∷uracil phosphoribosyl transferase suicide fusion gene ( yCD∷UPRT ) can be labeled with Venofer, an iron oxide carbohydrate nanoparticle. Venofer labeling did not affect cell proliferation or the ability to home to tumors. All Venofer-labeled MSCs released exosomes that contained iron oxide. Furthermore, these exosomes were efficiently endocytosed by tumor cells. Exosomes from Venofer-labeled MSCs expressing the yCD∷UPRT gene in the presence of the prodrug 5-fluorocytosine inhibited tumor growth in a dose-dependent fashion. The treated tumor cells were also effectively ablated following induction of hyperthermia using an external alternating magnetic field. Cumulatively, we found that magnetic nanoparticles packaged into MSC exosomes are efficiently endocytosed by tumor cells, facilitating targeted tumor cell ablation via magnetically induced hyperthermia.

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Visualization and tracking of tumour extracellular vesicle delivery and RNA translation using multiplexed reporters

Cited by 474 publications

References 65 publications

Exosome secretion promotes chemotaxis of cancer cells

Exosome secretion promotes chemotaxis of cancer cells

Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

Human mesenchymal stem cell-derived iron oxide exosomes allow targeted ablation of tumor cells via magnetic hyperthermia

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