Combinatorial targeting of cancer bone metastasis using mRNA engineered stem cellsResearch in context
Background: Bone metastases are common and devastating to cancer patients. Existing treatments do not specifically target the disease sites and are therefore ineffective and systemically toxic. Here we present a new strategy to treat bone metastasis by targeting both the cancer cells (“the seed”), a...
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| Format: | Article |
| Language: | English |
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Elsevier
2019-07-01
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| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396419304281 |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Aude I. Segaliny Jason L. Cheng Henry P. Farhoodi Michael Toledano Chih Chun Yu Beatrice Tierra Leanne Hildebrand Linan Liu Michael J. Liao Jaedu Cho Dongxu Liu Lizhi Sun Gultekin Gulsen Min-Ying Su Robert L. Sah Weian Zhao |
| spellingShingle |
Aude I. Segaliny Jason L. Cheng Henry P. Farhoodi Michael Toledano Chih Chun Yu Beatrice Tierra Leanne Hildebrand Linan Liu Michael J. Liao Jaedu Cho Dongxu Liu Lizhi Sun Gultekin Gulsen Min-Ying Su Robert L. Sah Weian Zhao Combinatorial targeting of cancer bone metastasis using mRNA engineered stem cellsResearch in context EBioMedicine |
| author_facet |
Aude I. Segaliny Jason L. Cheng Henry P. Farhoodi Michael Toledano Chih Chun Yu Beatrice Tierra Leanne Hildebrand Linan Liu Michael J. Liao Jaedu Cho Dongxu Liu Lizhi Sun Gultekin Gulsen Min-Ying Su Robert L. Sah Weian Zhao |
| author_sort |
Aude I. Segaliny |
| title |
Combinatorial targeting of cancer bone metastasis using mRNA engineered stem cellsResearch in context |
| title_short |
Combinatorial targeting of cancer bone metastasis using mRNA engineered stem cellsResearch in context |
| title_full |
Combinatorial targeting of cancer bone metastasis using mRNA engineered stem cellsResearch in context |
| title_fullStr |
Combinatorial targeting of cancer bone metastasis using mRNA engineered stem cellsResearch in context |
| title_full_unstemmed |
Combinatorial targeting of cancer bone metastasis using mRNA engineered stem cellsResearch in context |
| title_sort |
combinatorial targeting of cancer bone metastasis using mrna engineered stem cellsresearch in context |
| publisher |
Elsevier |
| series |
EBioMedicine |
| issn |
2352-3964 |
| publishDate |
2019-07-01 |
| description |
Background: Bone metastases are common and devastating to cancer patients. Existing treatments do not specifically target the disease sites and are therefore ineffective and systemically toxic. Here we present a new strategy to treat bone metastasis by targeting both the cancer cells (“the seed”), and their surrounding niche (“the soil”), using stem cells engineered to home to the bone metastatic niche and to maximise local delivery of multiple therapeutic factors. Methods: We used mesenchymal stem cells engineered using mRNA to simultaneously express P-selectin glycoprotein ligand-1 (PSGL-1)/Sialyl-Lewis X (SLEX) (homing factors), and modified versions of cytosine deaminase (CD) and osteoprotegerin (OPG) (therapeutic factors) to target and treat breast cancer bone metastases in two mouse models, a xenograft intratibial model and a syngeneic model of spontaneous bone metastasis. Findings: We first confirmed that MSC engineered using mRNA produced functional proteins (PSGL-1/SLEX, CD and OPG) using various in vitro assays. We then demonstrated that mRNA-engineered MSC exhibit enhanced homing to the bone metastatic niche likely through interactions between PSGL-1/SLEX and P-selectin expressed on tumour vasculature. In both the xenograft intratibial model and syngeneic model of spontaneous bone metastasis, engineered MSC can effectively kill tumour cells and preserve bone integrity. The engineered MSC also exhibited minimal toxicity in vivo, compared to its non-targeted chemotherapy counterpart (5-fluorouracil). Interpretation: Our combinatorial targeting of both the cancer cells and the niche represents a simple, safe and effective way to treat metastatic bone diseases, otherwise difficult to manage with existing strategies. It can also be applied to other cell types (e.g., T cells) and cargos (e.g., genome editing components) to treat a broad range of cancer and other complex diseases. Fund: National Institutes of Health, National Cancer Institute of the National Institutes of Health, Department of Defense, California Institute of Regenerative Medicine, National Science Foundation, Baylx Inc., and Fondation ARC pour la recherche sur le cancer. Keywords: Bone metastases, Cell therapy, Mesenchymal stem cell, mRNA engineering, Combination therapy |
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http://www.sciencedirect.com/science/article/pii/S2352396419304281 |
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doaj-ef5c77d618da4610b3aa536523f284312020-11-25T02:18:19ZengElsevierEBioMedicine2352-39642019-07-01453957Combinatorial targeting of cancer bone metastasis using mRNA engineered stem cellsResearch in contextAude I. Segaliny0Jason L. Cheng1Henry P. Farhoodi2Michael Toledano3Chih Chun Yu4Beatrice Tierra5Leanne Hildebrand6Linan Liu7Michael J. Liao8Jaedu Cho9Dongxu Liu10Lizhi Sun11Gultekin Gulsen12Min-Ying Su13Robert L. Sah14Weian Zhao15Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA; Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA 92697, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92697, USA; Edwards Life Sciences Center for Advanced Cardiovascular Technology, University of California, Irvine, Irvine, CA 92697, USA; Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USASue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA; Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA 92697, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92697, USA; Edwards Life Sciences Center for Advanced Cardiovascular Technology, University of California, Irvine, Irvine, CA 92697, USA; Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USASue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA; Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA 92697, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92697, USA; Edwards Life Sciences Center for Advanced Cardiovascular Technology, University of California, Irvine, Irvine, CA 92697, USA; Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USASue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA; Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA 92697, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92697, USA; Edwards Life Sciences Center for Advanced Cardiovascular Technology, University of California, Irvine, Irvine, CA 92697, USA; Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USASue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA; Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA 92697, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92697, USA; Edwards Life Sciences Center for Advanced Cardiovascular Technology, University of California, Irvine, Irvine, CA 92697, USA; Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USADepartment of Bioengineering, University of California, San Diego, San Diego, CA 92093, USASue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA; Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA 92697, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92697, USA; Edwards Life Sciences Center for Advanced Cardiovascular Technology, University of California, Irvine, Irvine, CA 92697, USA; Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USASue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA; Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA 92697, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92697, USA; Edwards Life Sciences Center for Advanced Cardiovascular Technology, University of California, Irvine, Irvine, CA 92697, USA; Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USASue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA; Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA 92697, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92697, USA; Edwards Life Sciences Center for Advanced Cardiovascular Technology, University of California, Irvine, Irvine, CA 92697, USA; Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USADepartment of Radiological Sciences, University of California, Irvine, Irvine, CA 92697, USADepartment of Civil and Environmental Engineering, University of California, Irvine, Irvine, CA 92697, USADepartment of Civil and Environmental Engineering, University of California, Irvine, Irvine, CA 92697, USADepartment of Radiological Sciences, University of California, Irvine, Irvine, CA 92697, USADepartment of Radiological Sciences, University of California, Irvine, Irvine, CA 92697, USADepartment of Bioengineering, University of California, San Diego, San Diego, CA 92093, USASue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA; Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA 92697, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92697, USA; Edwards Life Sciences Center for Advanced Cardiovascular Technology, University of California, Irvine, Irvine, CA 92697, USA; Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA; Corresponding author at: Sue & Bill Gross Hall CIRM Institute, 845 Health Sciences Road, Suite 3027, Irvine, CA 92697, USA.Background: Bone metastases are common and devastating to cancer patients. Existing treatments do not specifically target the disease sites and are therefore ineffective and systemically toxic. Here we present a new strategy to treat bone metastasis by targeting both the cancer cells (“the seed”), and their surrounding niche (“the soil”), using stem cells engineered to home to the bone metastatic niche and to maximise local delivery of multiple therapeutic factors. Methods: We used mesenchymal stem cells engineered using mRNA to simultaneously express P-selectin glycoprotein ligand-1 (PSGL-1)/Sialyl-Lewis X (SLEX) (homing factors), and modified versions of cytosine deaminase (CD) and osteoprotegerin (OPG) (therapeutic factors) to target and treat breast cancer bone metastases in two mouse models, a xenograft intratibial model and a syngeneic model of spontaneous bone metastasis. Findings: We first confirmed that MSC engineered using mRNA produced functional proteins (PSGL-1/SLEX, CD and OPG) using various in vitro assays. We then demonstrated that mRNA-engineered MSC exhibit enhanced homing to the bone metastatic niche likely through interactions between PSGL-1/SLEX and P-selectin expressed on tumour vasculature. In both the xenograft intratibial model and syngeneic model of spontaneous bone metastasis, engineered MSC can effectively kill tumour cells and preserve bone integrity. The engineered MSC also exhibited minimal toxicity in vivo, compared to its non-targeted chemotherapy counterpart (5-fluorouracil). Interpretation: Our combinatorial targeting of both the cancer cells and the niche represents a simple, safe and effective way to treat metastatic bone diseases, otherwise difficult to manage with existing strategies. It can also be applied to other cell types (e.g., T cells) and cargos (e.g., genome editing components) to treat a broad range of cancer and other complex diseases. Fund: National Institutes of Health, National Cancer Institute of the National Institutes of Health, Department of Defense, California Institute of Regenerative Medicine, National Science Foundation, Baylx Inc., and Fondation ARC pour la recherche sur le cancer. Keywords: Bone metastases, Cell therapy, Mesenchymal stem cell, mRNA engineering, Combination therapyhttp://www.sciencedirect.com/science/article/pii/S2352396419304281 |