Molecular Network Analysis of Endometriosis Reveals a Role for c-Jun–Regulated Macrophage Activation

Michael T Beste, Nicole Pfäffle-Doyle, Emily A Prentice, Stephanie N Morris, Stephanie Morris, Douglas A Lauffenburger, Keith Isaacson, Keith B Isaacson, Linda G Griffith
Science translational medicine · 2014 · vol. 6(222) , pp. 222ra16 · doi:10.1126/scitranslmed.3007988 · PMID:24500404 · W2018820961
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Abstract

Clinical management of endometriosis is limited by the complex relationship between symptom severity, heterogeneous surgical presentation, and variability in clinical outcomes. As a complement to visual classification schemes, molecular profiles of disease activity may improve risk stratification to better inform treatment decisions and identify new approaches to targeted treatment. We use a network analysis of information flow within and between inflammatory cells to discern consensus behaviors characterizing patient subpopulations. Unsupervised multivariate analysis of cytokine profiles quantified by multiplex immunoassays identified a subset of patients with a shared "consensus signature" of 13 elevated cytokines that was associated with common clinical features of endometriosis, but was not observed among patient subpopulations defined by morphologic presentation alone. Enrichment analysis of consensus markers reinforced the primacy of peritoneal macrophage infiltration and activation, which was demonstrably elevated in ex vivo cultures. Although familiar targets of the nuclear factor κB family emerged among overrepresented transcriptional binding sites for consensus markers, our analysis provides evidence for an unexpected contribution from c-Jun, c-Fos, and AP-1 effectors of mitogen-associated kinase signaling. Their crucial involvement in propagation of macrophage-driven inflammatory networks was confirmed via targeted inhibition of upstream kinases. Collectively, these analyses suggest a clinically relevant inflammatory network that may serve as an objective measure for guiding treatment decisions for endometriosis management, and in the future may provide a mechanistic endpoint for assessing efficacy of new agents aimed at curtailing inflammatory mechanisms that drive disease progression.

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Condition tags

mesh:D004715endometriosis

MeSH descriptors

Endometriosis Endometriosis Gene Regulatory Networks Macrophage Activation Proto-Oncogene Proteins c-jun Adult Biomarkers Biomarkers Biopsy, Needle Cytokines Cytokines Endometriosis Female Gene Expression Regulation Genome, Human Genome, Human Humans Inflammation Inflammation Macrophage Activation

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