Parallelized multidimensional analytic framework applied to mammary epithelial cells uncovers regulatory principles in EMT.

Autor: Paul I; Department of Biochemistry, Boston University School of Medicine, Boston University, 71 East Concord Street, Boston, MA, 02118, USA., Bolzan D; Department of Computer Science, University of Miami, 1356 Memorial Drive, Coral Gables, FL, 33146, USA., Youssef A; Graduate Program in Bioinformatics, Boston University, 24 Cummington Mall, Boston, MA, 02215, USA., Gagnon KA; Department of Biomedical Engineering, Boston University, 44 Cummington Mall, Boston, MA, 02215, USA., Hook H; Department of Biology, Boston University, 24 Cummington Mall, Boston, MA, 02115, USA.; Biological Design Center, Boston University, 610 Commonwealth Avenue, Boston, MA, 02215, USA., Karemore G; Advanced Analytics, Novo Nordisk A/S, 2760, Måløv, Denmark., Oliphant MUJ; Cancer Research Institute, Department of Medicine, Beth Israel  Deaconess Medical Center, Boston, MA, 02115, USA., Lin W; Department of Biochemistry, Boston University School of Medicine, Boston University, 71 East Concord Street, Boston, MA, 02118, USA., Liu Q; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, R3E 0J9, Canada., Phanse S; Department of Biochemistry, Boston University School of Medicine, Boston University, 71 East Concord Street, Boston, MA, 02118, USA., White C; Department of Biochemistry, Boston University School of Medicine, Boston University, 71 East Concord Street, Boston, MA, 02118, USA., Padhorny D; Department of Applied Mathematics and Statistics, Stony Brook University, 11794, Stony Brook, NY, USA.; Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY, 11794, USA., Kotelnikov S; Department of Applied Mathematics and Statistics, Stony Brook University, 11794, Stony Brook, NY, USA.; Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY, 11794, USA., Chen CS; Department of Biomedical Engineering, Boston University, 44 Cummington Mall, Boston, MA, 02215, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, 3 Blackfan Circle, Boston, MA, 02115, USA., Hu P; Department of Biochemistry, Western University, London, ON, N6A 5C1, Canada., Denis GV; Boston Medical Center Cancer Center, Boston University, Boston University, 72 East Concord Street, Boston, MA, 02118, USA., Kozakov D; Department of Applied Mathematics and Statistics, Stony Brook University, 11794, Stony Brook, NY, USA.; Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY, 11794, USA., Raught B; Discovery Tower (TMDT), 101 College St, Rm. 9-701A, University of Toronto, Toronto, ON, M5G 1L7, Canada., Siggers T; Department of Biology, Boston University, 24 Cummington Mall, Boston, MA, 02115, USA.; Biological Design Center, Boston University, 610 Commonwealth Avenue, Boston, MA, 02215, USA., Wuchty S; Department of Computer Science, University of Miami, 1356 Memorial Drive, Coral Gables, FL, 33146, USA., Muthuswamy SK; Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA., Emili A; Department of Biochemistry, Boston University School of Medicine, Boston University, 71 East Concord Street, Boston, MA, 02118, USA. emili@ohsu.edu.; Department of Biology, Charles River Campus, Boston University, Life Science & Engineering (LSEB-602), 24 Cummington Mall, Boston, MA, 02215, USA. emili@ohsu.edu.; Division of Oncological Sciences, Knight Cancer Institute, Oregon Health and Science University, Portland, USA. emili@ohsu.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Feb 08; Vol. 14 (1), pp. 688. Date of Electronic Publication: 2023 Feb 08.
DOI: 10.1038/s41467-023-36122-x
Abstrakt: A proper understanding of disease etiology will require longitudinal systems-scale reconstruction of the multitiered architecture of eukaryotic signaling. Here we combine state-of-the-art data acquisition platforms and bioinformatics tools to devise PAMAF, a workflow that simultaneously examines twelve omics modalities, i.e., protein abundance from whole-cells, nucleus, exosomes, secretome and membrane; N-glycosylation, phosphorylation; metabolites; mRNA, miRNA; and, in parallel, single-cell transcriptomes. We apply PAMAF in an established in vitro model of TGFβ-induced epithelial to mesenchymal transition (EMT) to quantify >61,000 molecules from 12 omics and 10 timepoints over 12 days. Bioinformatics analysis of this EMT-ExMap resource allowed us to identify; -topological coupling between omics, -four distinct cell states during EMT, -omics-specific kinetic paths, -stage-specific multi-omics characteristics, -distinct regulatory classes of genes, -ligand-receptor mediated intercellular crosstalk by integrating scRNAseq and subcellular proteomics, and -combinatorial drug targets (e.g., Hedgehog signaling and CAMK-II) to inhibit EMT, which we validate using a 3D mammary duct-on-a-chip platform. Overall, this study provides a resource on TGFβ signaling and EMT.
(© 2023. The Author(s).)
Databáze: MEDLINE
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