Combinatorial targeting of cancer bone metastasis using mRNA engineered stem cells

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

doi:10.1016/j.ebiom.2019.06.047

Combinatorial targeting of cancer bone metastasis using mRNA engineered stem cells

EBioMedicine. 2019 Jul:45:39-57. doi: 10.1016/j.ebiom.2019.06.047. Epub 2019 Jul 4.

Authors

Affiliations

¹ Sue 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.
² Department of Bioengineering, University of California, San Diego, San Diego, CA 92093, USA.
³ Department of Radiological Sciences, University of California, Irvine, Irvine, CA 92697, USA.
⁴ Department of Civil and Environmental Engineering, University of California, Irvine, Irvine, CA 92697, USA.
⁵ Sue 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. Electronic address: weianz@uci.edu.

Abstract

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; Combination therapy; Mesenchymal stem cell; mRNA engineering.

MeSH terms

Animals
Bone Neoplasms / genetics
Bone Neoplasms / pathology
Bone Neoplasms / secondary
Bone Neoplasms / therapy*
Breast Neoplasms / genetics
Breast Neoplasms / pathology
Breast Neoplasms / therapy*
Cell Engineering
Cell Line, Tumor
Cytosine Deaminase / genetics
Female
Genetic Therapy*
Humans
Membrane Glycoproteins / genetics
Mesenchymal Stem Cell Transplantation*
Mesenchymal Stem Cells
Mice
Osteoprotegerin / genetics
P-Selectin / genetics
RAW 264.7 Cells
RNA, Messenger / genetics
RNA, Messenger / therapeutic use
Sialyl Lewis X Antigen / genetics
Xenograft Model Antitumor Assays

Substances

Membrane Glycoproteins
Osteoprotegerin
P-Selectin
P-selectin ligand protein
RNA, Messenger
SELP protein, human
Sialyl Lewis X Antigen
Cytosine Deaminase

Abstract

MeSH terms

Substances

Grants and funding