TRAIL-coated leukocytes that kill cancer cells in the circulation

Mitchell, Michael J.; Wayne, Elizabeth; Rana, Kuldeepsinh; Schaffer, Chris B.; King, Michael R.

doi:10.1073/pnas.1316312111

Cited by 182 publications

(211 citation statements)

References 47 publications

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“…Such functionalized oil surface could create a high local concentration of the ligands and lead to more efficient interactions with the receptors on the cell surface (Fig. 3D) (26), similar to the high apoptosis rate induced by TRAIL-coated leukocytes in the work by Mitchell et al (27).…”

Section: Resultssupporting

confidence: 55%

One-pot system for synthesis, assembly, and display of functional single-span membrane proteins on oil–water interfaces

Yunker

Asahara

Hung

et al. 2015

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

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Single-span membrane proteins (ssMPs) represent approximately one-half of all membrane proteins and play important roles in cellular communications. However, like all membrane proteins, ssMPs are prone to misfolding and aggregation because of the hydrophobicity of transmembrane helices, making them difficult to study using common aqueous solution-based approaches. Detergents and membrane mimetics can solubilize membrane proteins but do not always result in proper folding and functionality. Here, we use cell-free protein synthesis in the presence of oil drops to create a one-pot system for the synthesis, assembly, and display of functional ssMPs. Our studies suggest that oil drops prevent aggregation of some in vitro-synthesized ssMPs by allowing these ssMPs to localize on oil surfaces. We speculate that oil drops may provide a hydrophobic interior for cotranslational insertion of the transmembrane helices and a fluidic surface for proper assembly and display of the ectodomains. These functionalized oil drop surfaces could mimic cell surfaces and allow ssMPs to interact with cell surface receptors under an environment closest to cell-cell communication. Using this approach, we showed that apoptosis-inducing human transmembrane proteins, FasL and TRAIL, synthesized and displayed on oil drops induce apoptosis of cultured tumor cells. In addition, we take advantage of hydrophobic interactions of transmembrane helices to manipulate the assembly of ssMPs and create artificial clusters on oil drop surfaces. Thus, by coupling protein synthesis with self-assembly at the water-oil interface, we create a platform that can use recombinant ssMPs to communicate with cells.embrane proteins populate the surfaces of cells and allow cells to sense and interact with their external environments. Membrane proteins constitute 25-30% of all proteins identified in sequenced genomes, and understanding their functions is important, because they represent the majority of current drug targets (1). Conventionally, function is inferred from structural studies of membrane proteins; these studies involve expression and purification of natural or recombinant membrane proteins followed by crystallization. However, membrane proteins are notoriously hard to work with because of their hydrophobic domains that can cause misfolding and aggregation (2). Consequently, detergents and membrane mimetics (3) are used to solubilize membrane proteins. To avoid cytotoxicity caused by in vivo expression and enable highthroughput production, cell-free systems are used to express membrane proteins in vitro (4-7). Despite recent progresses, understanding the functions of membrane proteins is still a lengthy and difficult process.Here, we develop a one-pot approach for synthesis, assembly, and display of single-span membrane proteins (ssMPs) for direct functional studies. ssMPs contain a single transmembrane (TM) helix that anchors the hydrophilic ectodomains on the membrane surface; ssMPs represent approximately one-half of all membrane proteins and are involved ...

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Section: Resultssupporting

confidence: 55%

One-pot system for synthesis, assembly, and display of functional single-span membrane proteins on oil–water interfaces

Yunker

Asahara

Hung

et al. 2015

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

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“…Second, to overcome the ethical concerns and cell scarcity limitations associated with NSCs (6, 7), here we have demonstrated the efficacy of adipose-derived stem cells as an abundant and easily accessible autologous cell source for targeting infiltrating GBM and microsatellites over long distances in vivo. Third, membrane-bound TRAIL was chosen as a therapeutic agent overexpressed by polymeric nanoparticles, which markedly augment receptor clustering and apoptosis stimulation in cancer cells (30,31). Last, patient-derived GBM xenograft cells were used rather than immortalized cell lines, which have been shown to better at preserving tumor phenotype and predicting clinically relevant outcomes (26).…”

Section: Discussionmentioning

confidence: 99%

“…Potential reasons for the lack of clinical efficacy may include insufficient tumor exposure (16,17) and/or weak engagement of the extrinsic pathway (10,13). We have chosen membrane display of TRAIL, which could more faithfully mimic the endogenous ligand, and markedly augment receptor clustering and apoptosis stimulation in cancer cells (30,31). Indeed, our results showed polymeric nanoparticles-induced TRAIL overexpressing led to effective targeting of intracranial brain tumor and microsatellite tumor cells in a patientderived glioblastoma orthotopic xenograft models, paving the way for clinical translation of this innovative therapeutic approach.…”

Section: Discussionmentioning

confidence: 99%

Nanoparticle engineered TRAIL-overexpressing adipose-derived stem cells target and eradicate glioblastoma via intracranial delivery

Jiang

Fitch

Wang

et al. 2016

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

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Glioblastoma multiforme (GBM) is one of the most intractable of human cancers, principally because of the highly infiltrative nature of these neoplasms. Tracking and eradicating infiltrating GBM cells and tumor microsatellites is of utmost importance for the treatment of this devastating disease, yet effective strategies remain elusive. Here we report polymeric nanoparticle-engineered human adipose-derived stem cells (hADSCs) overexpressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as drug-delivery vehicles for targeting and eradicating GBM cells in vivo. Our results showed that polymeric nanoparticle-mediated transfection led to robust up-regulation of TRAIL in hADSCs, and that TRAIL-expressing hADSCs induced tumor-specific apoptosis. When transplanted in a mouse intracranial xenograft model of patient-derived glioblastoma cells, hADSCs exhibited long-range directional migration and infiltration toward GBM tumor. Importantly, TRAIL-overexpressing hADSCs inhibited GBM growth, extended survival, and reduced the occurrence of microsatellites. Repetitive injection of TRAIL-overexpressing hADSCs significantly prolonged animal survival compared with single injection of these cells. Taken together, our data suggest that nanoparticle-engineered TRAIL-expressing hADSCs exhibit the therapeutically relevant behavior of "seek-and-destroy" tumortropic migration and could be a promising therapeutic approach to improve the treatment outcomes of patients with malignant brain tumors.nanoparticle | adipose-derived stem cells | TRAIL | glioblastoma | tumor microsatellites

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“…þ cells have been recently tested in preclinical setting to deliver TRAIL, with the aim of optimizing bioavailability and stability of this molecule (10)(11)(12)(13)(14)(15). An innovate option to deliver TRAIL could be to embed it within vesicular structures directly generated by TRAIL-expressing cells.…”

Section: Introductionmentioning

confidence: 99%

TNF-Related Apoptosis-Inducing Ligand (TRAIL)–Armed Exosomes Deliver Proapoptotic Signals to Tumor Site

Rivoltini

Chiodoni

Squarcina

et al. 2016

Clinical Cancer Research

160

120

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Purpose: Exosomes deliver signals to target cells and could thus be exploited as an innovative therapeutic tool. We investigated the ability of membrane TRAIL-armed exosomes to deliver proapoptotic signals to cancer cells and mediate growth inhibition in different tumor models.Experimental Methods and Results: K562 cells, transduced with lentiviral human membrane TRAIL, were used for the production of TRAIL þ exosomes, which were studied by nanoparticle tracking analysis, cytofluorimetry, immunoelectronmicroscopy, Western blot, and ELISA. In vitro, TRAIL þ exosomes induced more pronounced apoptosis (detected by Annexin V/ propidium iodide and activated caspase-3) in TRAIL-death receptor (DR)5 þ cells (SUDHL4 lymphoma and INT12 melanoma), with respect to the DR5 À DR4 þ KMS11 multiple myeloma. Intratumor injection of TRAIL þ exosomes, but not mock exosomes, induced growth inhibition of SUDHL4 (68%) and INT12 (51%), and necrosis in KMS11 tumors. After rapid blood clearance, systemically administered TRAIL þ exosomes accumulated in the liver, lungs, and spleen and homed to the tumor site, leading to a significant reduction of tumor growth (58%) in SUDHL4-bearing mice. The treatment of INT12-bearing animals promoted tumor necrosis and a not statistically significant tumor volume reduction. In KMS11-bearing mice, despite massive perivascular necrosis, no significant tumor growth inhibition was detected.Conclusions: TRAIL-armed exosomes can induce apoptosis in cancer cells and control tumor progression in vivo. Therapeutic efficacy was particularly evident in intratumor setting, while depended on tumor model upon systemic administration. Thanks to their ability to deliver multiple signals, exosomes thus represent a promising therapeutic tool in cancer.

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TRAIL-coated leukocytes that kill cancer cells in the circulation

Cited by 182 publications

References 47 publications

One-pot system for synthesis, assembly, and display of functional single-span membrane proteins on oil–water interfaces

One-pot system for synthesis, assembly, and display of functional single-span membrane proteins on oil–water interfaces

Nanoparticle engineered TRAIL-overexpressing adipose-derived stem cells target and eradicate glioblastoma via intracranial delivery

TNF-Related Apoptosis-Inducing Ligand (TRAIL)–Armed Exosomes Deliver Proapoptotic Signals to Tumor Site

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