Platelet mediated TRAIL delivery for efficiently targeting circulating tumor cells

Ortiz-Otero, Nerymar; Marshall, Jocelyn R.; Lash, Bradley; King, Michael R.

doi:10.1039/d0na00271b

Cited by 18 publications

(13 citation statements)

References 34 publications

(50 reference statements)

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“…Dissemination of circulating tumor cells (CTCs) is supported by platelets, which bind to CTCs during circulation and protect them from the harsh forces of the circulatory system [ 96 , 97 , 98 ]. In circulation, CTCs induce platelet activation and aggregation, becoming enveloped with platelets to shield them not only from fluid shear stress in blood flow but from the immune system and TNF-α-mediated cytotoxicity [ 99 ].…”

Section: Disseminationmentioning

confidence: 99%

Channeling the Force: Piezo1 Mechanotransduction in Cancer Metastasis

Dombroski

Hope

Sarna

et al. 2021

Cells

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Cancer metastasis is one of the leading causes of death worldwide, motivating research into identifying new methods of preventing cancer metastasis. Recently there has been increasing interest in understanding how cancer cells transduce mechanical forces into biochemical signals, as metastasis is a process that consists of a wide range of physical forces. For instance, the circulatory system through which disseminating cancer cells must transit is an environment characterized by variable fluid shear stress due to blood flow. Cancer cells and other cells can transduce physical stimuli into biochemical responses using the mechanosensitive ion channel Piezo1, which is activated by membrane deformations that occur when cells are exposed to physical forces. When active, Piezo1 opens, allowing for calcium flux into the cell. Calcium, as a ubiquitous second-messenger cation, is associated with many signaling pathways involved in cancer metastasis, such as angiogenesis, cell migration, intravasation, and proliferation. In this review, we discuss the roles of Piezo1 in each stage of cancer metastasis in addition to its roles in immune cell activation and cancer cell death.

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Section: Disseminationmentioning

confidence: 99%

Channeling the Force: Piezo1 Mechanotransduction in Cancer Metastasis

Dombroski

Hope

Sarna

et al. 2021

Cells

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“…This figure was created by the authors for this article Ex-vivo treatment of blood samples from Met-pa A cone-and-plate viscometer was used to apply shear stress to the blood samples as an ex-vivo CTC microenvironment. This experimental setting has been extensively used by our research group to better characterize the efficacy of CTC-targeted therapeutic agents [17,19,23,24]. An estimated 1-2 mL of blood aliquots were treated with 40 μL (~290 μg/mL of TRAIL) of vehicle control and TRAIL-liposomal solution and then placed in a cone-and-plate viscometer (Brookfield LVDVII) and sheared for 4 h. The cone-and-plate viscometers were incubated with 2 mL of 5% BSA for 30 min to block nonspecific interactions with the surface.…”

Section: Ctc and Caf Isolation From Met-pamentioning

confidence: 99%

Chemotherapy-induced release of circulating-tumor cells into the bloodstream in collective migration units with cancer-associated fibroblasts in metastatic cancer patients

Ortiz-Otero¹,

Marshall²,

Lash³

et al. 2020

BMC Cancer

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Background Recent studies have shown that chemotherapy destabilizes the blood vasculature and increases circulating tumor cell (CTC) influx into the circulation of metastatic cancer patients (Met-pa). CTCs are a precursor of cancer metastasis, in which they can migrate as single CTCs or as CTC clusters with stromal cells such as cancer-associated fibroblasts (CAFs) as cell aggregates. Methods Blood samples were collected from 52 Met-pa, and the number of CTC and CAF was determined along with the temporal fluctuation of these through the chemotherapy treatment. Results In this study, CTC level was found to increase two-fold from the initial level after 1 cycle of chemotherapy and returned to baseline after 2 cycles of chemotherapy. Importantly, we determined for the first time that circulating CAF levels correlate with worse prognosis and a lower probability of survival in Met-pa. Based on the CTC release induced by chemotherapy, we evaluated the efficacy of our previously developed cancer immunotherapy to eradicate CTCs from Met-pa blood using an ex vivo approach and demonstrate this could kill over 60% of CTCs. Conclusion Collectively, we found that CAF levels in Met-pa serve as a predictive biomarker for cancer prognosis. Additionally, we demonstrate the efficacy of our therapy to kill primary CTCs for a range of cancer types, supporting its potential use as an anti-metastasis therapy in the clinical setting.

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“…41 TRAIL nanoparticles can be attached to many different types of bloodcirculating cells to increase the efficacy of in vivo delivery. [42][43][44] A gap in TRAIL-mediated material therapies, however, has been to understand how optimize the density of TRAIL to maximize apoptosis. As our approach can be readily incorporated into the aforementioned nanoparticles or cellular designs, we foresee that including investigations into TRAIL surface density for these and other nanoparticle-based therapies would help further improve TRAIL efficacy for cancer therapy and push TRAIL to success in the clinic.…”

Section: Discussionmentioning

confidence: 99%

Lipid phase separation in vesicles enhances TRAIL-mediated cytotoxicity

Peruzzi

Sant'Anna

et al. 2021

Preprint

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Ligand spatial presentation and density play important roles in many signaling pathways mediated by cell receptors and are critical parameters when designing protein-conjugated therapeutic nanoparticles. Currently, Janus particles are most often used to spatially control ligand conjugation, but the technological challenge of manufacturing Janus particles limits adoption for translational applications. Here, we demonstrate that lipid phase separation can be used to spatially control protein presentation onto lipid vesicles. We used this system to study the density dependence of TNF-related apoptosis inducing ligand (TRAIL), a model therapeutic protein that exhibits greater cytotoxicity to cancer cells when conjugated onto a vesicle surface than when administered as a soluble protein. Using assays for apoptosis and caspase activity, we show that phase separated TRAIL vesicles induced higher cytotoxicity to Jurkat cancer cells than uniformly-conjugated TRAIL vesicles, and enhanced cytotoxicity was dependent on the TRAIL domain density. We then assessed this relationship in other cancer cell lines and demonstrated that phase separated TRAIL vesicles only enhanced cytotoxicity through one TRAIL receptor, DR5, while another TRAIL receptor, DR4, was unaffected by the TRAIL density. These results indicate unique signaling requirements for each TRAIL receptor and how TRAIL therapy could be tailored depending on the relative levels of expression for cancer receptors of interest. Overall, this work demonstrates a readily adoptable method to control protein conjugation and density on bilayer vesicles that can be easily adopted to other therapeutic nanoparticle systems to improve receptor signaling of nanoparticles targeted to cancer and diseased cells.

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Platelet mediated TRAIL delivery for efficiently targeting circulating tumor cells

Abstract: Liposomal formulation to deliver TNF-related apoptosis-inducing ligand (TRAIL) to platelets via von Willebrand Factor (vWF) interaction. TRAIL-coated platelets killed circulating tumor cells (CTCs) in the bloodstream to reduce cancer metastasis.

Cited by 18 publications

References 34 publications

Channeling the Force: Piezo1 Mechanotransduction in Cancer Metastasis

Channeling the Force: Piezo1 Mechanotransduction in Cancer Metastasis

Chemotherapy-induced release of circulating-tumor cells into the bloodstream in collective migration units with cancer-associated fibroblasts in metastatic cancer patients

Lipid phase separation in vesicles enhances TRAIL-mediated cytotoxicity

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