A new way to study the altered activity of molecular scissors in living models of cancer
Researchers led by Ludwig MIT’s Sangeeta Bhatia reported in an October issue of Nature Communications their development of an integrated set of methods to measure, at various scales, the activity of specific proteases—enzymes that snip protein molecules and are dysregulated in cancer. Studying enzyme activity in living cancerous tissue provides insight on their pathological roles and reveals clues to appropriately targeting specific enzymes for therapy. Sangeeta and her colleagues used a mouse model of Alk-positive lung cancer to study how targeted therapy affected the behavior of proteases in tumors. Applying multiplexed nanosensors and machine learning to analyze protease activity in vivo in lung tumors, the researchers observed extensive dysregulation of proteases, and zeroed in on the enhanced cleavage of one peptide nanosensor for further study. Analysis of enzymatic activity in tumors mapped this enhanced protease activity to their vasculature. The researchers also showed that the rate of nanosensor cleavage diminishes quickly in response to targeted therapy. Using a novel, high-throughput method to isolate and characterize proteolytically active cells, Sangeeta and colleagues uncovered a pro-angiogenic phenotype in those that cleave the nanosensor’s peptide sequence. This work offers a widely applicable framework for studying protease dysregulation in cancer and highlights the therapeutic potential of targeting the tumor microenvironment along with cancer cells.