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

John A Wrobel; Ling Xie; Li Wang; Cui Liu; Naim Rashid; Kristalyn K Gallagher; Yan Xiong; Kyle D Konze; Jian Jin; Michael L Gatza; Xian Chen

doi:10.1016/j.isci.2019.07.001

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

iScience. 2019 Jul 26:17:359-378. doi: 10.1016/j.isci.2019.07.001. Epub 2019 Jul 4.

Authors

John A Wrobel¹, Ling Xie¹, Li Wang¹, Cui Liu², Naim Rashid³, Kristalyn K Gallagher⁴, Yan Xiong¹, Kyle D Konze⁵, Jian Jin⁵, Michael L Gatza⁶, Xian Chen⁷

Affiliations

¹ Department of Biochemistry & Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² Department of Biochemistry & Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
³ Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biostatistics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Breast Surgical Oncology and Oncoplastics, UNC Surgical Breast Care Program, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁵ Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁶ Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA.
⁷ Department of Biochemistry & Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: xianc@email.unc.edu.

Abstract

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.

Keywords: Biological Sciences; Cancer; Cancer Systems Biology.

Abstract

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