In Vivo Imaging Reveals Extracellular Vesicle-Mediated Phenocopying of Metastatic Behavior

Zomer, Anoek; Maynard, Carrie; Verweij, Frederik J.; Kamermans, Alwin; Schäfer, Ronny; Beerling, Evelyne; Schiffelers, Raymond M.; Wit, Elzo de; Berenguer, Jordi; Ellenbroek, Saskia I.J.; Würdinger, Thomas; Pegtel, D. Michiel; Rheenen, Jacco van

doi:10.1016/j.cell.2015.04.042

Cited by 740 publications

(737 citation statements)

References 31 publications

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“…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. This method has been successfully used several times 117, 118…”

Section: Modular Design Of Internal Contentsmentioning

confidence: 99%

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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Section: Modular Design Of Internal Contentsmentioning

confidence: 99%

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

2018

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“…Published data indicate that EVs share with viruses an important function that played a critical role in evolution, namely delivering bioactive material from one cell to another (7,8,20,21). Specific combinations of lipids and proteins, in particular, tetraspanins (22), in the EV membrane can mediate specific targeting of vesicles to recipient cells and may determine the ability of vesicles to fuse with cellular membranes.…”

Section: "Mister Postman": What Do Evs and Viruses Delivermentioning

confidence: 99%

Extracellular vesicles and viruses: Are they close relatives?

Hoen

Cremer

Gallo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

412

390

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Extracellular vesicles (EVs) released by various cells are small phospholipid membrane-enclosed entities that can carry miRNA. They are now central to research in many fields of biology because they seem to constitute a new system of cell–cell communication. Physical and chemical characteristics of many EVs, as well as their biogenesis pathways, resemble those of retroviruses. Moreover, EVs generated by virus-infected cells can incorporate viral proteins and fragments of viral RNA, being thus indistinguishable from defective (noninfectious) retroviruses. EVs, depending on the proteins and genetic material incorporated in them, play a significant role in viral infection, both facilitating and suppressing it. Deciphering the mechanisms of EV-cell interactions may facilitate the design of EVs that inhibit viral infection and can be used as vehicles for targeted drug delivery.

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“…S10). This observation suggests communication between cocultured cells (32) and may have important implication for the dynamics of malignant states in populations. However, further elucidation is required to account for cell-cell communication, bystander effect, or gene/drug penetration when addressing the targeting of spatially constrained cells.…”

Section: Discussionmentioning

confidence: 95%

Cellular heterogeneity mediates inherent sensitivity–specificity tradeoff in cancer targeting by synthetic circuits

Morel

Shtrahman

Rotter

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Synthetic gene circuits are emerging as a versatile means to target cancer with enhanced specificity by combinatorial integration of multiple expression markers. Such circuits must also be tuned to be highly sensitive because escape of even a few cells might be detrimental. However, the error rates of decision-making circuits in light of cellular variability in gene expression have so far remained unexplored. Here, we measure the single-cell response function of a tunable logic AND gate acting on two promoters in heterogeneous cell populations. Our analysis reveals an inherent tradeoff between specificity and sensitivity that is controlled by the AND gate amplification gain and activation threshold. We implement a tumor-mimicking cellculture model of cancer cells emerging in a background of normal ones, and show that molecular parameters of the synthetic circuits control specificity and sensitivity in a killing assay. This suggests that, beyond the inherent tradeoff, synthetic circuits operating in a heterogeneous environment could be optimized to efficiently target malignant state with minimal loss of specificity.synthetic gene circuits | cellular heterogeneity | cancer gene therapy | cell-state targeting | mammalian synthetic biology T he design of gene circuits capable of precisely targeting cancer cells is a major challenge in synthetic biology (1-3), in light of the prospects of using engineered viruses for cancer gene therapy (4), or designing T cells expressing chimeric antigen receptors (CAR-T) (5). Ideally, targeting circuits must be highly sensitive to eradicate all cancer cells, and sufficiently specific to protect surrounding tissues. Gene expression markers that are hyperactive in cancer but not in healthy cells are natural candidates for cancer gene therapy (6). However, a single marker does not suffice because it might be moderately active in normal cells, which would result in incorrect identification. Combining multiple markers improves specificity because a weakly active one will buffer the others by thresholding (7,8), as in Boolean logic circuits converting graded inputs into digital-like output (9-14). The response function of such circuits--input/output activation threshold, amplitude, and sharpness--can be tuned by DNA specificity, promoter design, or protein-protein affinity (15, 16).We previously reported a dual-promoter integrator (DPI) as a logic AND gate to combine the activity of two cancer-specific promoters, and express a reporter or killer gene only when both promoters are decidedly active (17). Subsequently, others used a multiinput logic circuit based on microRNAs to target cancer (18). This Boolean approach provides reliable results on average, but ignores the heterogeneity of cell states. Input values may span a continuum due to expression noise (19,20) and cancer heterogeneity (21). Furthermore, so-called synthetic circuits are not truly digital all-or-none, but rather analog systems that produce continuous signals using transcription factors, expression regulators, and machi...

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In Vivo Imaging Reveals Extracellular Vesicle-Mediated Phenocopying of Metastatic Behavior

Cited by 740 publications

References 31 publications

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

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

Extracellular vesicles and viruses: Are they close relatives?

Cellular heterogeneity mediates inherent sensitivity–specificity tradeoff in cancer targeting by synthetic circuits

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