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Sci Transl Med. 2017 Jul 26;9(400). pii: eaan2966. doi: 10.1126/scitranslmed.aan2966.

Mechanoresponsive stem cells to target cancer metastases through biophysical cues.

Liu L1,2,3,4,5,6, Zhang SX1,2,3,4,5,6, Liao W1,2,3,4,5,6, Farhoodi HP1,2,3,4,5,6, Wong CW1,2,3,4,5,6, Chen CC1,2,3,4,5,6, Ségaliny AI1,2,3,4,5,6, Chacko JV5, Nguyen LP1,2,3,4,5,6, Lu M1,2,3,4,5,6, Polovin G1,2,3,4,5,6, Pone EJ1,2,3,4,5,6, Downing TL1,5, Lawson DA1,3,7, Digman MA5,8,9, Zhao W10,2,3,4,5,6.

Author information

1
Sue and Bill Gross Stem Cell Research Center, 845 Health Sciences Road, University of California, Irvine, Irvine, CA 92697, USA.
2
Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA 92697, USA.
3
Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92697, USA.
4
Edwards Life Sciences Center for Advanced Cardiovascular Technology, University of California, Irvine, Irvine, CA 92697, USA.
5
Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA.
6
Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
7
Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697, USA.
8
Laboratory for Fluorescence Dynamics, University of California, Irvine, Irvine, CA 92697, USA.
9
Centre for Bioactive Discovery in Health and Ageing, School of Science and Technology, University of New England, Armidale, New South Wales 2351, Australia.
10
Sue and Bill Gross Stem Cell Research Center, 845 Health Sciences Road, University of California, Irvine, Irvine, CA 92697, USA. weianz@uci.edu.

Abstract

Despite decades of effort, little progress has been made to improve the treatment of cancer metastases. To leverage the central role of the mechanoenvironment in cancer metastasis, we present a mechanoresponsive cell system (MRCS) to selectively identify and treat cancer metastases by targeting the specific biophysical cues in the tumor niche in vivo. Our MRCS uses mechanosensitive promoter-driven mesenchymal stem cell (MSC)-based vectors, which selectively home to and target cancer metastases in response to specific mechanical cues to deliver therapeutics to effectively kill cancer cells, as demonstrated in a metastatic breast cancer mouse model. Our data suggest a strong correlation between collagen cross-linking and increased tissue stiffness at the metastatic sites, where our MRCS is specifically activated by the specific cancer-associated mechano-cues. MRCS has markedly reduced deleterious effects compared to MSCs constitutively expressing therapeutics. MRCS indicates that biophysical cues, specifically matrix stiffness, are appealing targets for cancer treatment due to their long persistence in the body (measured in years), making them refractory to the development of resistance to treatment. Our MRCS can serve as a platform for future diagnostics and therapies targeting aberrant tissue stiffness in conditions such as cancer and fibrotic diseases, and it should help to elucidate mechanobiology and reveal what cells "feel" in the microenvironment in vivo.

PMID:
28747514
PMCID:
PMC5890431
DOI:
10.1126/scitranslmed.aan2966
[Indexed for MEDLINE]
Free PMC Article

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