DSBSO-Based XL-MS Analysis of Breast Cancer PDX Tissues to Delineate Protein Interaction Network in Clinical Samples

Fenglong Jiao, Clinton Yu, Andrew Wheat, Lijun Chen, Tung Shing Mamie Lih, Hui Zhang, Lan Huang

Research output: Contribution to journalArticlepeer-review

Abstract

Protein-protein interactions (PPIs) are fundamental to understanding biological systems as protein complexes are the active molecular modules critical for carrying out cellular functions. Dysfunctional PPIs have been associated with various diseases including cancer. Systems-wide PPI analysis not only sheds light on pathological mechanisms, but also represents a paradigm in identifying potential therapeutic targets. In recent years, cross-linking mass spectrometry (XL-MS) has emerged as a powerful tool for defining endogenous PPIs of cellular networks. While proteome-wide studies have been performed in cell lysates, intact cells and tissues, applications of XL-MS in clinical samples have not been reported. In this study, we adopted a DSBSO-based in vivo XL-MS platform to map interaction landscapes from two breast cancer patient-derived xenograft (PDX) models. As a result, we have generated a PDX interaction network comprising 2,557 human proteins and identified interactions unique to breast cancer subtypes. Interestingly, most of the observed differences in PPIs correlated well with protein abundance changes determined by TMT-based proteome quantitation. Collectively, this work has demonstrated the feasibility of XL-MS analysis in clinical samples, and established an analytical workflow for tissue cross-linking that can be generalized for mapping PPIs from patient samples in the future to dissect disease-relevant cellular networks.

Original languageEnglish (US)
Pages (from-to)3269-3279
Number of pages11
JournalJournal of proteome research
Volume23
Issue number8
DOIs
StatePublished - Aug 2 2024

Keywords

  • Alkyne-A-DSBSO
  • PDX
  • PPI
  • XL-MS
  • breast cancer

ASJC Scopus subject areas

  • General Chemistry
  • Biochemistry

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