Multi-omic Dissection of Oncogenically Active Epiproteomes Identifies Drivers of Proliferative and Invasive Breast Tumors

• Published in: iScience Vol. 17; pp. 359 - 378
• Main Authors: Wrobel, John A., Xie, Ling, Wang, Li, Liu, Cui, Rashid, Naim, Gallagher, Kristalyn K., Xiong, Yan, Konze, Kyle D., Jin, Jian, Gatza, Michael L., Chen, Xian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.07.2019; Elsevier
• Subjects: Biological Sciences; Cancer; Cancer Systems Biology; Biological Sciences; Cancer Systems Biology; Cancer
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2019.07.001

Proliferative and invasive breast tumors evolve heterogeneously in individual patients, posing significant challenges in identifying new druggable targets for precision, effective therapy. Here we present a functional multi-omics method, interaction-Correlated Multi-omic Aberration Patterning (iC-MAP), which dissects intra-tumor heterogeneity and identifies in situ the oncogenic consequences of multi-omics aberrations that drive proliferative and invasive tumors. First, we perform chromatin activity-based chemoproteomics (ChaC) experiments on breast cancer (BC) patient tissues to identify genetic/transcriptomic alterations that manifest as oncogenically active proteins. ChaC employs a biotinylated small molecule probe that specifically binds to the oncogenically active histone methyltransferase G9a, enabling sorting/enrichment of a G9a-interacting protein complex that represents the predominant BC subtype in a tissue. Second, using patient transcriptomic/genomic data, we retrospectively identified some G9a interactor-encoding genes that showed individualized iC-MAP. Our iC-MAP findings represent both new diagnostic/prognostic markers to identify patient subsets with incurable metastatic disease and targets to create individualized therapeutic strategies. [Display omitted] •ChaC dissects tumor heterogeneity for identifying oncogenic-active proteins•An oncogenic-active G9a-interactome represents the invasive tumor in a tissue•iC-MAP identifies multi-omics aberrations that drive invasive tumors•Patient-specific iC-MAP of select interactor genes are of prognostic value Biological Sciences; Cancer Systems Biology; Cancer