title: Epigenomic Deconvolution of Breast Tumors Reveals Metabolic Coupling between Constituent Cell Types.
abstract: Cancer progression depends on both cell-intrinsic processes and interactions between different cell types. However, large-scale assessment of cell type composition and molecular profiles of individual cell types within tumors remains challenging. To address this, we developed epigenomic deconvolution (EDec), an in silico method that infers cell type composition of complex tissues as well as DNA methylation and gene transcription profiles of constituent cell types. By applying EDec to The Cancer Genome Atlas (TCGA) breast tumors, we detect changes in immune cell infiltration related to patient prognosis, and a striking change in stromal fibroblast-to-adipocyte ratio across breast cancer subtypes. Furthermore, we show that a less adipose stroma tends to display lower levels of mitochondrial activity and to be associated with cancerous cells with higher levels of oxidative metabolism. These findings highlight the role of stromal composition in the metabolic coupling between distinct cell types within tumors.
authors.affiliation: Molecular and Human Genetics Department, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA; Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA. Electronic address: onuchic@bcm.edu.
authors.forename: Vitor
authors.initials: V
authors.lastname: Onuchic
authors.affiliation: Department of Pharmacology and Chemical Biology, Magee Womens Research Institute, University of Pittsburgh Cancer Institute, 204 Craft Avenue, B705, Pittsburgh, PA 15213, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Hartmaier
authors.affiliation: Department of Pharmacology and Chemical Biology, Magee Womens Research Institute, University of Pittsburgh Cancer Institute, 204 Craft Avenue, B705, Pittsburgh, PA 15213, USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Boone
authors.affiliation: RainDance Technologies, Inc., 749 Middlesex Turnpike, Billerica, MA 01821, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Samuels
authors.affiliation: Molecular and Human Genetics Department, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Ronak Y
authors.initials: RY
authors.lastname: Patel
authors.affiliation: Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, 200 1st Street SW, Rochester, MN 55905, USA.
authors.forename: Wendy M
authors.initials: WM
authors.lastname: White
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA.
authors.forename: Vesna D
authors.initials: VD
authors.lastname: Garovic
authors.affiliation: Department of Pharmacology and Chemical Biology, Magee Womens Research Institute, University of Pittsburgh Cancer Institute, 204 Craft Avenue, B705, Pittsburgh, PA 15213, USA.
authors.forename: Steffi
authors.initials: S
authors.lastname: Oesterreich
authors.affiliation: Molecular and Human Genetics Department, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Matt E
authors.initials: ME
authors.lastname: Roth
authors.affiliation: Department of Pharmacology and Chemical Biology, Magee Womens Research Institute, University of Pittsburgh Cancer Institute, 204 Craft Avenue, B705, Pittsburgh, PA 15213, USA.
authors.forename: Adrian V
authors.initials: AV
authors.lastname: Lee
authors.affiliation: Molecular and Human Genetics Department, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA; Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA. Electronic address: amilosav@bcm.edu.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Milosavljevic
mesh_terms: D000273:Adipose Tissue / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D003198:Computer Simulation; D019175:DNA Methylation / Q000235:genetics; D018450:Disease Progression; D057890:Epigenomics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D010084:Oxidation-Reduction; D010641:Phenotype; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA; D017154:Stromal Cells / Q000473:pathology; D059016:Tumor Microenvironment / Q000235:genetics
keywords: DNA methylation; Warburg effect; breast cancer; cancer; cell type composition; deconvolution; gene expression; heterotypic interaction; metabolic coupling; metabolism