A Novel Biomarker for Disease: Using Biophysical Cues to Detect, Treat, and Study Cancer

Author(s): Zhang, Shirley | Advisor(s): Zhao, Weian | Abstract: In recent years, cancer research has increasingly focused on the mechanobiology of the tumor microenvironment (TME). Biophysical cues, such as mechanical properties or forces within a tumor, have proven to be just as important in influencing cell behavior as biochemical or molecular cues. The TME, often characterized by increased fibrillary collagen deposition and crosslinking and increased elastic modulus, has distinct biophysical cues which can act as a biomarker for cancer. Cells, with their innate ability to respond to differences in their mechanical environment, can thus be engineered to utilize biophysical cues to specifically target tumors. Using this ideology, we have created a mechano-responsive cell system (MRCS) to specifically home to and target cancer metastases and deliver therapeutics. MRCS engineered to selectively activate and express cytosine deaminase when in contact with increased substrate stiffness were able to locally convert an inactive prodrug to an active chemotherapeutic drug on tumor regions of metastatic lungs, with minimal off-target side effects on less stiff, healthy tissues. In addition to therapeutic applications, engineered cell sensors can be used as tools to study cancer mechanobiology. There remain many unanswered questions surrounding how the TME and resident cells affect each other. Currently available tools to measure mechanical properties of tissues at a cellular level are insufficient to answer these questions. Cell-based stiffness sensors which can report their response to their microenvironment are a potential new tool which can be used to address unknowns, such as how the TME evolves during cancer progression, how biophysical cues influence malignancy and metastasis, and if the different mechanical properties within a tumor contribute to tumor heterogeneity and drug resistance. This platform technology can also be applied to other diseases characterized by increased tissue stiffness, such as fibrosis. With the advancement of imaging and gene-editing technologies, as well as increasing awareness and interest in mechanomedicine, the potential applications of mechano-responsive cells are endless.