Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer

Kamerkar, Sushrut; LeBleu, Valerie S.; Sugimoto, Hikaru; Yang, Stephen C.; Ruivo, Carolina F.; Melo, Sónia A.; Lee, John; Kalluri, Raghu

doi:10.1038/nature22341

Cited by 2,023 publications

(1,793 citation statements)

References 52 publications

Supporting

Mentioning

1,762

Contrasting

Unclassified

Order By: Relevance

“…Recent advances in cellular genetic editing techniques such as CRISPR‐Cas9 could be harnessed to upregulate or augment intrinsic MSCs enzyme function before implantation in order to achieve maximal benefit. Alternatively, the growing field of exosomal/hydrogel engineering has shown growing promise as a novel, efficacious disease treatment strategy 71, 72. With increasing mechanistic insight, these treatment strategies may converge and be used to guide further studies aimed at engineering the optimal use of cells or cell components for future iterations of cell‐based therapy in MI/R injury.…”

Section: Discussionmentioning

confidence: 99%

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

Shin

Wang

Zemskova

et al. 2018

JAHA

View full text Add to dashboard Cite

BackgroundDuring myocardial ischemia/reperfusion (MI/R) injury, there is extensive release of immunogenic metabolites that activate cells of the innate immune system. These include ATP and AMP, which upregulate chemotaxis, migration, and effector function of early infiltrating inflammatory cells. These cells subsequently drive further tissue devitalization. Mesenchymal stromal cells (MSCs) are a potential treatment modality for MI/R because of their powerful anti‐inflammatory capabilities; however, the manner in which they regulate the acute inflammatory milieu requires further elucidation. CD73, an ecto‐5′‐nucleotidase, may be critical in regulating inflammation by converting pro‐inflammatory AMP to anti‐inflammatory adenosine. We hypothesized that MSC‐mediated conversion of AMP into adenosine reduces inflammation in early MI/R, favoring a micro‐environment that attenuates excessive innate immune cell activation and facilitates earlier cardiac recovery.Methods and ResultsAdult rats were subjected to 30 minutes of MI/R injury. MSCs were encapsulated within a hydrogel vehicle and implanted onto the myocardium. A subset of MSCs were pretreated with the CD73 inhibitor, α,β‐methylene adenosine diphosphate, before implantation. Using liquid chromatography/mass spectrometry, we found that MSCs increase myocardial adenosine availability following injury via CD73 activity. MSCs also reduce innate immune cell infiltration as measured by flow cytometry, and hydrogen peroxide formation as measured by Amplex Red assay. These effects were dependent on MSC‐mediated CD73 activity. Finally, through echocardiography we found that CD73 activity on MSCs was critical to optimal protection of cardiac function following MI/R injury.Conclusions MSC‐mediated conversion of AMP to adenosine by CD73 exerts a powerful anti‐inflammatory effect critical for cardiac recovery following MI/R injury.

show abstract

Section: Discussionmentioning

confidence: 99%

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

Shin

Wang

Zemskova

et al. 2018

JAHA

View full text Add to dashboard Cite

show abstract

“…These exosomes harbour CD47 (a fundamental “don’t eat me” signal) on their surface, and were found to evade phagocytosis by circulating monocytes. This strategy could contribute to limiting the clearance of exosomes from circulation and enhance their accumulation in target tumour tissues [100]. …”

Section: Therapeutic Applications Of Surface-modified Evsmentioning

confidence: 99%

Extracellular vesicles as a platform for membrane‐associated therapeutic protein delivery

Yang

Hong

Cho

et al. 2018

J of Extracellular Vesicle

190

148

View full text Add to dashboard Cite

Membrane proteins are of great research interest, particularly because they are rich in targets for therapeutic application. The suitability of various membrane proteins as targets for therapeutic formulations, such as drugs or antibodies, has been studied in preclinical and clinical studies. For therapeutic application, however, a protein must be expressed and purified in as close to its native conformation as possible. This has proven difficult for membrane proteins, as their native conformation requires the association with an appropriate cellular membrane. One solution to this problem is to use extracellular vesicles as a display platform. Exosomes and microvesicles are membranous extracellular vesicles that are released from most cells. Their membranes may provide a favourable microenvironment for membrane proteins to take on their proper conformation, activity, and membrane distribution; moreover, membrane proteins can cluster into microdomains on the surface of extracellular vesicles following their biogenesis. In this review, we survey the state-of-the-art of extracellular vesicle (exosome and small-sized microvesicle)-based therapeutics, evaluate the current biological understanding of these formulations, and forecast the technical advances that will be needed to continue driving the development of membrane protein therapeutics.

show abstract

“…EVs with αv integrin‐specific arginine–glycine–aspartic acid peptides and loaded with doxorubicin selectively inhibited breast cancer progression, whereas unmodified EVs were mostly eliminated without affecting the tumor 47. Modified EVs have also demonstrated potential in specific targeting of oncogenic KRAS for tumor therapy 109. Recently, tumor necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL) was attached to the membrane of EVs, and these TRAIL‐armed EVs were found to inhibit tumor growth via transmission of proapoptotic signals 110…”

Section: Modular Design Of Surface Proteinsmentioning

confidence: 99%

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

2018

View full text Add to dashboard Cite

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.

show abstract

Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer

Cited by 2,023 publications

References 52 publications

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

Extracellular vesicles as a platform for membrane‐associated therapeutic protein delivery

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

Contact Info

Product

Resources

About