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Multiscale profiling of enzyme activity in cancer

View ORCID ProfileAva P. Soleimany, Jesse D. Kirkpatrick, Cathy S. Wang, Alex M. Jaeger, Susan Su, Santiago Naranjo, Qian Zhong, Christina M. Cabana, Tyler Jacks, View ORCID ProfileSangeeta N. Bhatia
doi: https://doi.org/10.1101/2021.11.11.468288
Ava P. Soleimany
1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
2Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA
3Program in Biophysics, Harvard University, Boston, MA
4Microsoft Research New England, Cambridge, MA
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  • ORCID record for Ava P. Soleimany
Jesse D. Kirkpatrick
1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
2Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA
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Cathy S. Wang
1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
5Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA
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Alex M. Jaeger
1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
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Susan Su
1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
6Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA
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Santiago Naranjo
1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
7Department of Biology, Massachusetts Institute of Technology, Cambridge, MA
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Qian Zhong
1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
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Christina M. Cabana
1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
7Department of Biology, Massachusetts Institute of Technology, Cambridge, MA
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Tyler Jacks
1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
7Department of Biology, Massachusetts Institute of Technology, Cambridge, MA
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Sangeeta N. Bhatia
1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
2Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA
8Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA
9Department of Medicine, Brigham and Women’s Hospital, Boston, MA
10Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
11Wyss Institute at Harvard University, Boston, MA
12Howard Hughes Medical Institute, Cambridge, MA
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  • ORCID record for Sangeeta N. Bhatia
  • For correspondence: sbhatia@mit.edu
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Abstract

Diverse processes in cancer are mediated by enzymes, which most proximally exert their function through their activity. Methods to quantify enzyme activity, rather than just expression, are therefore critical to our ability to understand the pathological roles of enzymes in cancer and to harness this class of biomolecules as diagnostic and therapeutic targets. Here we present an integrated set of methods for measuring specific enzyme activities across the organism, tissue, and cellular levels, which we unify into a methodological hierarchy to facilitate biological discovery. We focus on proteases for method development and validate our approach through the study of tumor progression and treatment response in an autochthonous model of Alk-mutant lung cancer. To quantitatively measure activity dynamics over time, we engineered multiplexed, peptide-based nanosensors to query protease activity in vivo. Machine learning analysis of sensor measurements revealed dramatic protease dysregulation in lung cancer, including significantly enhanced proteolytic cleavage of one peptide, S1 (Padj < 0.0001), which returned to healthy levels within three days after initiation of targeted therapy. Next, to link these organism-level observations to the in situ context, we established a multiplexed assay for on-tissue localization of enzyme activity and pinpointed S1 cleavage to endothelial cells and pericytes of the tumor vasculature. Lastly, to directly link enzyme activity measurements to cellular phenotype, we designed a high-throughput method to isolate and characterize proteolytically active cells, uncovering profound upregulation of pro-angiogenic transcriptional programs in S1-positive cells. Together, these methods allowed us to discover that protease production by angiogenic vasculature responds rapidly to targeted therapy against oncogene-addicted tumor cells, identifying a highly dynamic interplay between tumor cells and their microenvironment. This work provides a generalizable framework to functionally characterize enzyme activity in cancer.

Competing Interest Statement

T.J. is a member of the Board of Directors of Amgen and Thermo Fisher Scientific and a co-founder of Dragonfly Therapeutics and T2 Biosystems; serves on the Scientific Advisory Board of Dragonfly Therapeutics, SQZ Biotech, and Skyhawk Therapeutics; and is President of Break Through Cancer. T.J.'s laboratory currently receives funding from Johnson & Johnson and The Lustgarten Foundation, but these funds did not support the research described in this manuscript. S.N.B. is a director at Vertex; is a co-founder of and consultant for Glympse Bio, Satellite Bio, and Cend Therapeutics; holds equity in Glympse Bio, Satellite Bio, Cend Therapeutics, and Catalio Capital; consults for Moderna; and receives sponsored research funding from Johnson & Johnson. Funds from Johnson & Johnson to S.N.B.'s laboratory supported the research described in this manuscript.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted November 12, 2021.
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Multiscale profiling of enzyme activity in cancer
Ava P. Soleimany, Jesse D. Kirkpatrick, Cathy S. Wang, Alex M. Jaeger, Susan Su, Santiago Naranjo, Qian Zhong, Christina M. Cabana, Tyler Jacks, Sangeeta N. Bhatia
bioRxiv 2021.11.11.468288; doi: https://doi.org/10.1101/2021.11.11.468288
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Multiscale profiling of enzyme activity in cancer
Ava P. Soleimany, Jesse D. Kirkpatrick, Cathy S. Wang, Alex M. Jaeger, Susan Su, Santiago Naranjo, Qian Zhong, Christina M. Cabana, Tyler Jacks, Sangeeta N. Bhatia
bioRxiv 2021.11.11.468288; doi: https://doi.org/10.1101/2021.11.11.468288

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