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- Menden, MP, et al.
(författare)
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Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2674-
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Tidskriftsartikel (refereegranskat)abstract
- The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.
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- Fischer, C, et al.
(författare)
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A miR-327-FGF10-FGFR2-mediated autocrine signaling mechanism controls white fat browning
- 2017
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8:1, s. 2079-
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the molecular mechanisms regulating beige adipocyte formation may lead to the development of new therapies to combat obesity. Here, we report a miRNA-based autocrine regulatory pathway that controls differentiation of preadipocytes into beige adipocytes. We identify miR-327 as one of the most downregulated miRNAs targeting growth factors in the stromal-vascular fraction (SVF) under conditions that promote white adipose tissue (WAT) browning in mice. Gain- and loss-of-function experiments reveal that miR-327 targets FGF10 to prevent beige adipocyte differentiation. Pharmacological and physiological β-adrenergic stimulation upregulates FGF10 levels and promotes preadipocyte differentiation into beige adipocytes. In vivo local delivery of miR-327 to WATs significantly compromises the beige phenotype and thermogenesis. Contrarily, systemic inhibition of miR-327 in mice induces browning and increases whole-body metabolic rate under thermoneutral conditions. Our data provide mechanistic insight into an autocrine regulatory signaling loop that regulates beige adipocyte formation and suggests that the miR-327–FGF10–FGFR2 signaling axis may be a therapeutic targets for treatment of obesity and metabolic diseases.
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- Kupers, LK, et al.
(författare)
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Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 1893-
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Tidskriftsartikel (refereegranskat)abstract
- Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from −183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10−7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10−74) and BMI in pregnancy (3/914, p = 1.13x10−3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.
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