UC Irvine

Cancer metastases are responsible for more than 90% of cancer deaths, however no current effective therapeutics directly and specifically targets them. The exclusive mechanical properties of metastatic niche offer an intriguing target for the development of treatments selectively targeting metastases. Systemically infused mesenchymal stem cells (MSCs) preferentially home to tumors. Besides, it has been established that tissue mechanical properties regulate MSC differentiation by driving expression of certain genes. We hypothesize that increased matrix stiffness is an essential property of the metastatic niche that can be targeted with MSC-based, mechano-responsive therapies. Here we presented, by targeting the mechano-environment of the metastatic niche, a new methodology for the treatment of cancer metastases, using promoter-driven, MSC-based vectors, named as mechano-responsive cell system (MRCS). Our data suggest that the MRCS homes to and targets cancer metastasis responding to specific mechanical microenvironment to deliver therapeutics, such as cytosine deaminase (CD) that locally activates the prodrug to kill cancer with minimal side-effects. Compared to MSCs expressing CD constitutively, MRCS not only treats metastatic breast cancer with reduced deleterious effects and more effective outcome, but may also serve as a platform technology for prospective application to therapies targeting abnormal tissue stiffness including fibrotic diseases.