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Updated: Aug 26, 2025
Quantitative Mass Spectrometric Profiling of Cancer-cell Proteomes Derived From Liquid and Solid Tumors
Published on: February 27, 2015
Multiscale profiling of protease activity in cancer
Ava P Amini1,2,3,4, Jesse D Kirkpatrick1,2, Cathy S Wang1,5
1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
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.
Insights
Researchers developed new methods to measure enzyme activity in lung cancer, finding specific protease activity in tumor blood vessels that drives tumor growth. This activity decreased with targeted therapy.
Area of Science:
- Biochemistry
- Oncology
- Biotechnology
Background:
- Enzymes play crucial roles in cancer, mediating diverse processes through their activity.
- High-fidelity methods for profiling enzyme activity are essential for understanding and targeting cancer.
- Protease dysregulation is implicated in various pathological conditions, including cancer.
Purpose of the Study:
- To present an integrated set of methods for measuring specific protease activities across scales.
- To study treatment response in an autochthonous model of Alk-mutant lung cancer using these methods.
- To link protease activity to cellular function and uncover its role in cancer progression.
Main Methods:
- Development of multiplexed nanosensors for in vivo protease activity analysis.
- Application of machine learning for analyzing protease activity dynamics.
- High-throughput isolation and characterization of proteolytically active cells.
- On-tissue localization techniques to pinpoint protease activity.
Main Results:
- Significant dysregulation of protease activity identified in Alk-mutant lung cancer.
- Enhanced cleavage of a specific peptide (S1) observed, which normalized with targeted therapy.
- S1 cleavage was localized to the tumor vasculature.
- S1-cleaving cells exhibited a pro-angiogenic phenotype.
Conclusions:
- The developed methods enable functional, multiscale characterization of protease dysregulation in cancer.
- Targeted therapy can effectively modulate specific protease activities linked to cancer progression.
- Understanding protease activity in the tumor microenvironment, particularly vasculature, is crucial for therapeutic strategies.
