Mechanoresponsive stem cells target cancer metastases
Metastases cause for over 90% of cancer related deaths, yet there are relatively few treatments available to patients whose cancer has spread from the original tumour. Surgical removal of metastases is rarely feasible and the heterogeneous nature of metastatic cancer may contribute to resistance to chemotherapy. In a new study, published in the journal Science Translational Medicine, researchers from the University of California, Irvine describe a strategy that uses the increased tissue stiffness of the extracellular matrix at metastatic sites to find and kill cancer cells.
The extracellular matrix (ECM) is a complex network of proteins, secreted factors and other extracellular molecules that contribute to tissue architecture, homeostasis and regeneration. This highly dynamic structure undergoes drastic biochemical and biomechanical modifications during development, organogenesis, tissue repair and disease progression, including cancer metastases. In the new study, Liu and colleagues have engineered a mechanoresponsive cell system (MRCS). These modified mesenchymal stem cells (MSCs) specifically interact with the stiffer tumour microenvironment and act as a vehicle for targeted delivery of anti-cancer agents. MSCs naturally have the ability to sense mechanical cues. Previous studies had shown that the YAP/TAZ protein moves from the cytoplasm to the nucleus in response to a stiff ECM. Here, the researchers engineered the cells so that nuclear YAP/TAZ activated expression of cytosine deaminase (CD), an enzyme necessary for the activation of chemotherapy precursor 5 –fluoricil (5-FU).
In vitro analysis confirmed the selective activation and tumor-killing effects of MRCS-CD in response to matrix stiffness. In addition, in vivo experimental data show that MRCS-CD can detect and infiltrate lung metastasis of breast cancer tumours in mice. Upon treatment with 5-FU, metastases shrunk and survival increased compared to control animals. MCSs that constitutively (always on) expressed CD, rather than only in response to the stiff ECM had similar anti-cancer effects. However, damage to normal tissue was much more wide-spread in these animals, suggesting that the mechanoreceptor adds a therapeutical benefit. The current study focusses on breastcancer lung metastases only, but the treatment has potential for other cancers as well as fibrotic diseases, where the physical properties of the tissue are also affected.
Original article: Science Translational Medicine
Digest for a general audience: UC Irvine website, Science Daily