Multiscale profiling of protease activity in cancer
Name
s41467-022-32988-5.pdf
Description
Published version
Size
3.2 MB
Format
Adobe PDF
Checksum (MD5)
8d9334c88df4a217e1abadd108e1014d
Author(s)
Amini, Ava P
Kirkpatrick, Jesse D
Wang, Cathy S
Jaeger, Alex M
Su, Susan
Naranjo, Santiago
Zhong, Qian
Cabana, Christina M
Jacks, Tyler
Bhatia, Sangeeta N
Date Issued
October 3, 2022
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Citation
Amini, Ava P, Kirkpatrick, Jesse D, Wang, Cathy S, Jaeger, Alex M, Su, Susan et al. 2022. "Multiscale profiling of protease activity in cancer." Nature Communications, 13 (1).
Version
Final published version
Abstract
AbstractDiverse 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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/s41467-022-32988-5
