Nanosensors target enzymes to monitor and study cancer

Good news! Cancer is history (soon)! Treating cancer at nanoscale precision with multiscale (space and time) analysis! Wow! Very impressive work! This is only the beginning!

It appears humans are finally understanding and outsmarting cancer at nanoscale!!!

"... Sensitive tools for measuring protein or gene expression, even on the single cell level, have helped researchers understand the different cell types present in a tumor’s microenvironment and how this composition changes after treatments. However, these assays don’t necessarily show which proteins are active or relevant to tumor progression, or allow clinicians to noninvasively monitor the progress of the disease or its response to treatment. A protein could be present in a cancer cell as a bystander, for example, but not an active participant in its cellular transformations. Enzymes, which catalyze biochemical reactions inside cells, may give a clearer picture of which genes or proteins to target at a particular time. ...

researchers ... have developed a set of enzyme-targeting nanoscale tools to monitor cancer progression and treatment response in real time, map enzyme activity to precise locations within a tumor, and isolate relevant cell populations for analysis. ...
the nanosensors could be used by clinicians to tailor treatments to a patient’s specific cancer, and to monitor cancer progression and treatment response, while researchers could use them to better understand the molecular biology of cancer and develop new tools to diagnose, track, and treat the disease ...

For several years, the ... laboratory has been developing noninvasive urine tests for the detection of cancer, including colon, ovarian, and lung cancer. The tests rely on nanoparticles that interact with tumor proteins called proteases. Proteases are a type of enzyme that act as molecular scissors to cleave proteins and break them down into smaller components. Proteases help cancer cells escape from tumors by cutting through the extracellular network of proteins that holds cells in place.

The nanoparticles are coated with peptides (short protein fragments) that target cancer-linked proteases. When the nanoparticles arrive at the tumor site, the peptides are cut and release biomarkers that can be detected in the urine.

In the current study, the researchers tested whether they could use this technology not just to detect cancer, but to track the development of cancer and its response to treatments accurately and sensitively over time. The team created a panel of 14 nanoparticles designed to target proteases overexpressed in non-small cell lung cancer induced in a mouse model. These nanoparticles had been adapted to release barcoded peptides when they encounter dysregulated enzymes in the tumor microenvironment.

Each nanosensor was able to track different patterns of protease activity, which changed dramatically as the tumor progressed. After treatment with a lung cancer-targeting drug, the researchers were able to find signs tumor regression quickly, within just three days of administering treatment. ...

Having identified nanosensors of interest, researchers mapped where in the tumor microenvironment the enzymes acting on these sensors were active. They adapted their nanoprobes to leave behind fluorescent tags when they are cleaved from the nanosensor, assigning different tags to different proteases. After applying the nanoprobes to samples of lung tissue, they looked for patterns in how the tags were distributed.

One tag resulted in a curious spindle-like pattern that turned out to belong to the tumor vasculature. Researchers pinpointed the protease activity to specific types of cells: endothelial cells, which line blood vessels, and pericytes, which regulate vascular function and are actively recruited in angiogenesis — one of the archetypal hallmarks of cancer cell growth. ...
Ultimately, however, the team envisions panels of nanoprobes targeting several important features of cancer simultaneously and noninvasively in patients. Other hallmarks of cancer include proliferative signaling, the evasion of growth suppressors, genome instability, resistance to cell death, deregulated metabolism, and activation of invasion and metastasis. Because cancer alters protease activity across all of these processes, the team’s nanoprobes could be designed to target these different processes, with the aim of providing a comprehensive picture of tumor activity driving the disease. ..."

From the abstract:

"Diverse processes in cancer are mediated by enzymes, which most proximally exert their function through their activity. High-fidelity methods to profile enzyme activity are therefore critical to understanding and targeting the pathological roles of enzymes in cancer. Here, we present an integrated set of methods for measuring specific protease activities across scales, and deploy these methods to study treatment response in an autochthonous model of Alk-mutant lung cancer. We leverage multiplexed nanosensors and machine learning to analyze in vivo protease activity dynamics in lung cancer, identifying significant dysregulation that includes enhanced cleavage of a peptide, S1, which rapidly returns to healthy levels with targeted therapy. Through direct on-tissue localization of protease activity, we pinpoint S1 cleavage to the tumor vasculature. To link protease activity to cellular function, we design a high-throughput method to isolate and characterize proteolytically active cells, uncovering a pro-angiogenic phenotype in S1-cleaving cells. These methods provide a framework for functional, multiscale characterization of protease dysregulation in cancer."

Nanosensors target enzymes to monitor and study cancer | MIT News | Massachusetts Institute of Technology By analyzing enzyme activity at the organism, tissue, and cellular scales, new sensors could provide new tools to clinicians and cancer researchers.

Multiscale profiling of protease activity in cancer (open access)

Fig. 1: Multiscale profiling of protease activity in cancer