Tognetti, Marco, Gabor, Attila, Yang, Mi, Cappelletti, Valentina, Windhager, Jonas ORCID: 0000-0002-2111-5291, Rueda, Oscar M., Charmpi, Konstantina, Esmaeilishirazifard, Elham, Bruna, Alejandra ORCID: 0000-0003-1214-9665, de Souza, Natalie, Caldas, Carlos, Beyer, Andreas, Picotti, Paola, Saez-Rodriguez, Julio ORCID: 0000-0002-8552-8976 and Bodenmiller, Bernd (2021). Deciphering the signaling network of breast cancer improves drug sensitivity prediction. Cell Syst., 12 (5). S. 401 - 431. CAMBRIDGE: CELL PRESS. ISSN 2405-4720

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Abstract

One goal of precision medicine is to tailor effective treatments to patients' specific molecular markers of disease. Here, we used mass cytometry to characterize the single-cell signaling landscapes of 62 breast cancer cell lines and five lines from healthy tissue. We quantified 34 markers in each cell line upon stimulation by the growth factor EGF in the presence or absence of five kinase inhibitors. These data-on more than 80 million single cells from 4,000 conditions-were used to fit mechanistic signaling network models that provide insight into how cancer cells process information. Our dynamic single-cell-based models accurately predicted drug sensitivity and identified genomic features associated with drug sensitivity, including a missense mutation in DDIT3 predictive of PI3K-inhibition sensitivity. We observed similar trends in genotype-drug sensitivity associations in patient-derived xenograft mouse models. This work provides proof of principle that patient-specific single-cell measurements and modeling could inform effective precision medicine strategies.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Tognetti, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gabor, AttilaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yang, MiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cappelletti, ValentinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Windhager, JonasUNSPECIFIEDorcid.org/0000-0002-2111-5291UNSPECIFIED
Rueda, Oscar M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Charmpi, KonstantinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Esmaeilishirazifard, ElhamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruna, AlejandraUNSPECIFIEDorcid.org/0000-0003-1214-9665UNSPECIFIED
de Souza, NatalieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caldas, CarlosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beyer, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Picotti, PaolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saez-Rodriguez, JulioUNSPECIFIEDorcid.org/0000-0002-8552-8976UNSPECIFIED
Bodenmiller, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-598191
DOI: 10.1016/j.cels.2021.04.002
Journal or Publication Title: Cell Syst.
Volume: 12
Number: 5
Page Range: S. 401 - 431
Date: 2021
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 2405-4720
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DATA-INDEPENDENT ACQUISITION; SOMATIC MUTATIONS; MEK INHIBITORS; DOUBLE-BLIND; RECEPTOR; ACTIVATION; GENE; PATHWAY; KINASE; MODELSMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59819

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