Synthetic biology-based cellular biomedical tattoo for detection of hypercalcemia associated with cancer
Science Translational Medicine • 18 Apr 2018 • Vol 10, Issue 437 • DOI: 10.1126/scitranslmed.aap8562
A melanin mark for hypercalcemia
Earlier detection of disease could help improve response to therapy. Blood calcium concentrations are elevated in several types of cancer, in addition to other diseases. Here, Tastanova et al. used synthetic biology and cell engineering to develop a sensor that detects hypercalcemia. Their implantable sensor consists of cells that express the calcium-sensing receptor and produce melanin in response to sustained elevated calcium in the blood. Melanin was visible as a dark pigment in the encapsulated cell constructs in vitro and could be detected when implanted in pig skin ex vivo. Melanin production was also observed in engineered cells implanted in mice bearing hypercalcemic breast and colon cancer tumors. This biomedical tattoo strategy could also potentially be used to noninvasively monitor response to treatment.
Abstract
Diagnosis marks the beginning of any successful therapy. Because many medical conditions progress asymptomatically over extended periods of time, their timely diagnosis remains difficult, and this adversely affects patient prognosis. Focusing on hypercalcemia associated with cancer, we aimed to develop a synthetic biology-inspired biomedical tattoo using engineered cells that would (i) monitor long-term blood calcium concentration, (ii) detect onset of mild hypercalcemia, and (iii) respond via subcutaneous accumulation of the black pigment melanin to form a visible tattoo. For this purpose, we designed cells containing an ectopically expressed calcium-sensing receptor rewired to a synthetic signaling cascade that activates expression of transgenic tyrosinase, which produces melanin in response to persistently increased blood Ca2+. We confirmed that the melanin-generated color change produced by this biomedical tattoo could be detected with the naked eye and optically quantified. The system was validated in wild-type mice bearing subcutaneously implanted encapsulated engineered cells. All animals inoculated with hypercalcemic breast and colon adenocarcinoma cells developed tattoos, whereas no tattoos were seen in animals inoculated with normocalcemic tumor cells. All tumor-bearing animals remained asymptomatic throughout the 38-day experimental period. Although hypercalcemia is also associated with other pathologies, our findings demonstrate that it is possible to detect hypercalcemia associated with cancer in murine models using this cell-based diagnostic strategy.
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Supplementary Material
Summary
Table S1. Plasmids used and designed in this study.
Table S2. Individual subject-level data.
Movie S1. Melanin production by HEKTyr cells.
Movie S2. HEKTattoo cells cultured in hypocalcemic medium.
Movie S3. HEKTattoo cells cultured in normocalcemic medium.
Movie S4. HEKTattoo cells cultured in mild hypercalcemic medium.
Movie S5. HEKTattoo cells cultured in moderate hypercalcemic medium.
MATLAB code
Resources
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Science Translational Medicine
Volume 10 | Issue 437
April 2018
April 2018
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Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Received: 2 September 2017
Accepted: 29 March 2018
Acknowledgments
We are grateful to H. Zulewski, P. Saxena, T. Rubic-Schneider, and J. Moggs for advice and critical comments on the manuscript, and we thank D. Zimmer and M.-D. Hussherr for conducting animal experiments. We are grateful to A. Alitalo for helping to design the animal study. We thank H.-M. Kaltenbach for his valuable support with statistical analyses. This work was supported by the National Centre of Competence in Research (NCCR) for Molecular Systems Engineering. Funding: This work was supported by a grant of the Swiss NCCR Molecular Systems Engineering to M. Fussenegger. Author contributions: A.T., M. Folcher, and M. Fussenegger designed the project and analyzed the results. A.T., M.M., T.H., and A.P. performed the experimental work. A.T., A.P., and M.S.T. designed and wrote the MATLAB code. A.T. and G.C. designed the animal experiments. A.T. and M. Fussenegger wrote the manuscript. Competing interests: The authors declare that they have no competing financial interests. Data and materials availability: All data necessary for the interpretation of results are included in the paper and the Supplementary Materials. Requests for additional information and materials should be directed to the corresponding author.
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