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      Whole-body tracking of single cells via positron emission tomography

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          Abstract

          In vivo molecular imaging can measure the average kinetics and movement routes of injected cells through the body. Yet owing to the non-specific accumulation of the contrast agent and its efflux from the cells, most such imaging methods suffer from inaccurate estimations of the distribution of the cells. Here, we show that single human breast cancer cells loaded with mesoporous silica nanoparticles concentrating the 68Ga radioisotope and injected in immunodeficient mice can be tracked in real time from the pattern of annihilation photons detected by positron emission tomography, with respect to anatomical landmarks derived from X-ray computed tomography. We show that the cells travelled at an average velocity of 50 mm/s and arrested in the lungs two-to-three seconds after tail-vein injection in the mice, which is consistent with the blood-flow rate. Single-cell tracking could be used to determine the kinetics of cell trafficking and arrest during the earliest phase of the metastatic cascade, the trafficking of immune cells during cancer immunotherapy, and the distribution of cells after transplantation.

          Abstract

          One-sentence editorial summary:

          The travelling kinetics of single cells loaded with mesoporous silica nanoparticles concentrating the 68Ga radioisotope and injected in mice can be tracked in real time from the pattern of coincident gamma-rays detected by positron emission tomography.

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          Most cited references37

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          CAR T cell immunotherapy for human cancer

          Adoptive T cell transfer (ACT) is a new area of transfusion medicine involving the infusion of lymphocytes to mediate antitumor, antiviral, or anti-inflammatory effects. The field has rapidly advanced from a promising form of immuno-oncology in preclinical models to the recent commercial approvals of chimeric antigen receptor (CAR) T cells to treat leukemia and lymphoma. This Review describes opportunities and challenges for entering mainstream oncology that presently face the CAR T field, with a focus on the challenges that have emerged over the past several years.
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            Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis.

            Circulating tumor cell clusters (CTC clusters) are present in the blood of patients with cancer but their contribution to metastasis is not well defined. Using mouse models with tagged mammary tumors, we demonstrate that CTC clusters arise from oligoclonal tumor cell groupings and not from intravascular aggregation events. Although rare in the circulation compared with single CTCs, CTC clusters have 23- to 50-fold increased metastatic potential. In patients with breast cancer, single-cell resolution RNA sequencing of CTC clusters and single CTCs, matched within individual blood samples, identifies the cell junction component plakoglobin as highly differentially expressed. In mouse models, knockdown of plakoglobin abrogates CTC cluster formation and suppresses lung metastases. In breast cancer patients, both abundance of CTC clusters and high tumor plakoglobin levels denote adverse outcomes. Thus, CTC clusters are derived from multicellular groupings of primary tumor cells held together through plakoglobin-dependent intercellular adhesion, and though rare, they greatly contribute to the metastatic spread of cancer. Copyright © 2014 Elsevier Inc. All rights reserved.
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              The physics of cancer: the role of physical interactions and mechanical forces in metastasis.

              Metastasis is a complex, multistep process responsible for >90% of cancer-related deaths. In addition to genetic and external environmental factors, the physical interactions of cancer cells with their microenvironment, as well as their modulation by mechanical forces, are key determinants of the metastatic process. We reconstruct the metastatic process and describe the importance of key physical and mechanical processes at each step of the cascade. The emerging insight into these physical interactions may help to solve some long-standing questions in disease progression and may lead to new approaches to developing cancer diagnostics and therapies.
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                Author and article information

                Journal
                101696896
                45929
                Nat Biomed Eng
                Nat Biomed Eng
                Nature biomedical engineering
                2157-846X
                20 May 2020
                15 June 2020
                August 2020
                15 December 2020
                : 4
                : 8
                : 835-844
                Affiliations
                [1 ]Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 94305, USA
                [2 ]Department of Radiology, Stanford University School of Medicine, Stanford, CA, 94305, USA
                [3 ]Department of Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA
                Author notes
                [* ]Corresponding author, pratx@ 123456stanford.edu

                Author contributions

                KOJ performed in vitro and in vivo experiments. TJK performed physical tests and processed data. JHY characterized nanoparticles and optimized their radiolabelling. SR imaged ex vivo specimens. WZ reconstructed CT images. BH contributed to the design of the methods. GP reconstructed dynamic cell trajectory data. KOJ and GP designed the study and wrote the manuscript. KRH, SSG and GP supervised the study.

                Article
                NIHMS1595342
                10.1038/s41551-020-0570-5
                7423763
                32541917
                4beea9e0-7bb7-4e4b-9eef-76676174838e

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