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Sensitive Spatiotemporal Tracking of Spontaneous Metastasis in Deep Tissues via a Genetically-Encoded Magnetic Resonance Imaging Reporter

Nyström, Nivin N. and McRae, Sean W. and Martinez, Francisco F. M. and Kelly, John J. and Scholl, Timothy J. and Ronald, John A. (2022) Sensitive Spatiotemporal Tracking of Spontaneous Metastasis in Deep Tissues via a Genetically-Encoded Magnetic Resonance Imaging Reporter. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20220222-706476000

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Abstract

Metastasis remains a poorly understood aspect of cancer biology and the leading cause of cancer-related death, yet most preclinical cancer studies do not examine metastasis, focusing solely on the primary tumor. One major factor contributing to this paradox is a gap in available tools for accurate spatiotemporal measurements of metastatic spread in vivo. Our objective was to develop an imaging reporter system that offers sensitive three-dimensional detection of cancer cells at high resolutions in live mice. We utilized organic anion-transporting polypeptide 1b3 (oatp1b3) as a magnetic resonance imaging (MRI) reporter gene to this end, and systematically optimized its framework for in vivo tracking of viable cancer cells in a spontaneous metastasis model. We were able to image metastasis on oatp1b3-MRI at the single lymph node level and continued to track its progression over time as cancer cells spread to multiple lymph nodes and different organ systems in single animals. While initial single lesions were successfully imaged in parallel via bioluminescence, later metastases were obscured by light scatter from the initial node. Importantly, we demonstrate and validate that 100-μm isotropic resolution MR images could detect micrometastases in lung tissue estimated to contain fewer than 10³ cancer cells. In summary, oatp1b3-MRI enables precise determination of lesion size and location over time and offers a path towards deep-tissue tracking of any oatp1b3-engineered cell type with combined high resolution, high sensitivity, 3D spatial information, and surrounding anatomical context.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2022.02.09.479610DOIArticle
ORCID:
AuthorORCID
Nyström, Nivin N.0000-0001-6288-6060
Scholl, Timothy J.0000-0002-0807-363X
Ronald, John A.0000-0003-3665-173X
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. Financial support for this manuscript was provided by Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grants (JAR RGPIN-2016-05420, TJS RGPIN-2017-06338), and an Ontario Institute for Cancer Research Investigator Award (TJS IA-028). NNN is grateful to have received financial support from a Natural Sciences and Engineering Research Council of Canada Postgraduate Research Scholarship (2017-2021), and as an Amgen Awardee of the Life Sciences Research Foundation (2021-present). The authors would also like to acknowledge David Reese for providing helpful resources, and the larger Cellular and Molecular Imaging Group at the Robarts Research Institute for insightful discussions. The authors would also like to acknowledge Karen Nygard and Reza Khazaee of the Biotron Facilities at the University of Western Ontario for their expertise on transmission electron microscopy, as well as Patrick Zakrzewski, Mohammed Farhoud, and Mat Brevard from EMIT Imaging Technologies for their expertise in cryo-fluorescence tomography. The authors have declared no competing interest.
Funders:
Funding AgencyGrant Number
Natural Sciences and Engineering Research Council of Canada (NSERC)RGPIN-2016-05420
Natural Sciences and Engineering Research Council of Canada (NSERC)RGPIN-2017-06338
Ontario Institute for Cancer ResearchUNSPECIFIED
Life Sciences Research FoundationUNSPECIFIED
Subject Keywords:Cancer, metastasis, imaging, cell tracking, reporter gene, magnetic resonance imaging, oatp1b3
DOI:10.1101/2022.02.09.479610
Record Number:CaltechAUTHORS:20220222-706476000
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220222-706476000
Official Citation:Sensitive Spatiotemporal Tracking of Spontaneous Metastasis in Deep Tissues via a Genetically-Encoded Magnetic Resonance Imaging Reporter Nivin N Nyström, Sean W McRae, Francisco FM Martinez, John J Kelly, Timothy J Scholl, John A Ronald bioRxiv 2022.02.09.479610; doi: https://doi.org/10.1101/2022.02.09.479610
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:113520
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:24 Feb 2022 17:48
Last Modified:24 Feb 2022 17:48

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