Synthetic biology-based cellular biomedical tattoo for detection of hypercalcemia associated with cancer

A biomedical tattoo composed of cells engineered to express a calcium-sensing receptor coupled to visible melanin production detects hypercalcemia. 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. 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.