A stiff punishment for tumors
In patients, tumor cells do not grow in isolation, and their behavior is regulated not only by their own biology but also by interactions with their microenvironment. A key part of the microenvironment is the extracellular matrix, which typically has a greater stiffness in tumors than in surrounding normal tissues. To take advantage of this, Liu et al. engineered mechanoresponsive mesenchymal stem cells to act as vehicles for cancer drug delivery. These engineered stem cells accumulated in tumors, delivering the first half of a two-part cancer therapy: the enzyme cytosine deaminase. A drug called 5-fluorocytosine was then delivered systemically, and cytosine deaminase in the tumors activated the drug, providing local anticancer activity with no off-target damage in mice.
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.