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Reverse Sensitivity Analysis for Identifying Predictive Proteomics Signatures of
Cancer


EMSL Project ID
51790

Abstract

Cancer is a complex disease in which genetic disruptions in cell signaling networks are known to play a significant role. A major aim of cancer systems biology is to build models that can predict the impact of these genetic disruptions to guide therapeutic interventions (i.e. personalized medicine). A prominent driver of cancer cell growth is signaling pathway deregulation
from mutations in key regulatory nodes and loss/gain in gene copy number (CNV). However, current mathematical modeling approaches do not adequately capture the impact of these genetic changes. Reasons for this include the poorly understood layers of regulation between gene expression and
protein activity, and limitations in most modeling and protein measurement technologies. In addition, there is a paucity of overarching hypotheses that can link specific gene expression or mutation patterns to the cancer phenotype. Recent work by our group has resolved some of the technical challenges that have hindered the application of proteomics technologies to cancer systems biology research. It has
also suggested a new approach for using quantitative proteomics data to understand mechanisms driving cancer cell behavior. Using an ultrasensitive, targeted proteomics platform that can measure both abundance and phosphorylation of proteins present at only hundreds of copies per cell, we found
that signaling pathways appeared to be controlled by only a limited number of key nodes whose activity is tightly regulated through low abundance and feedback phosphorylation. We propose to build on
these findings by critically testing the hypothesis that CNV and genetic mutations dysregulate signaling pathways in cancer by shifting control from tightly regulated nodes to poorly regulated ones. This will be
done by systematically identifying key regulatory nodes of normal and cancer cells using CRISPRa/i screens, determine the relationship between protein abundance and signaling pathway activities using
ultrasensitive targeted proteomics and phosphoproteomics and then use these data to semi-automatically generate mathematical models of the functional topology of the signaling pathways.

Project Details

Start Date
2020-12-01
End Date
2023-09-30
Status
Closed

Team

Principal Investigator

Weijun Qian
Institution
Pacific Northwest National Laboratory

Co-Investigator(s)

H Wiley
Institution
Environmental Molecular Sciences Laboratory

Team Members

Tujin Shi
Institution
Pacific Northwest National Laboratory