Molecular Network Analysis of Endometriosis Reveals a Role for c-Jun-Regulated Macrophage Activation
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...
| Main Authors: | , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
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American Association for the Advancement of Science (AAAS)
2014
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| Online Access: | http://hdl.handle.net/1721.1/88950 https://orcid.org/0000-0002-1801-5548 |
| _version_ | 1811074286810562560 |
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| author | Beste, Michael T. Pfaffle-Doyle, Nicole Prentice, Emily A. Lauffenburger, Douglas A. Morris, Stephanie N. Isaacson, Keith B. Griffith, Linda G. |
| author2 | Massachusetts Institute of Technology. Center for Gynepathology Research |
| author_facet | Massachusetts Institute of Technology. Center for Gynepathology Research Beste, Michael T. Pfaffle-Doyle, Nicole Prentice, Emily A. Lauffenburger, Douglas A. Morris, Stephanie N. Isaacson, Keith B. Griffith, Linda G. |
| author_sort | Beste, Michael T. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T09:46:40Z |
| format | Article |
| id | mit-1721.1/88950 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:46:40Z |
| publishDate | 2014 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/889502022-09-26T13:38:08Z Molecular Network Analysis of Endometriosis Reveals a Role for c-Jun-Regulated Macrophage Activation Beste, Michael T. Pfaffle-Doyle, Nicole Prentice, Emily A. Lauffenburger, Douglas A. Morris, Stephanie N. Isaacson, Keith B. Griffith, Linda G. Massachusetts Institute of Technology. Center for Gynepathology Research Massachusetts Institute of Technology. Department of Biological Engineering Beste, Michael T. Pfaffle-Doyle, Nicole Prentice, Emily A. Lauffenburger, Douglas A. Isaacson, Keith B. Griffith, Linda G. 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. National Institutes of Health (U.S.) (R01EB10246) Singapore-MIT Alliance United States. Army Research Office (Institute for Collaborative Biotechnologies W911NF-09-001) John D. and Catherine T. MacArthur Foundation 2014-08-21T15:24:11Z 2014-08-21T15:24:11Z 2014-02 2013-11 Article http://purl.org/eprint/type/JournalArticle 1946-6234 1946-6242 http://hdl.handle.net/1721.1/88950 Beste, M. T., N. Pfaffle-Doyle, E. A. Prentice, S. N. Morris, D. A. Lauffenburger, K. B. Isaacson, and L. G. Griffith. “Molecular Network Analysis of Endometriosis Reveals a Role for c-Jun-Regulated Macrophage Activation.” Science Translational Medicine 6, no. 222 (February 5, 2014): 222ra16–222ra16. https://orcid.org/0000-0002-1801-5548 en_US http://dx.doi.org/10.1126/scitranslmed.3007988 Science Translational Medicine Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for the Advancement of Science (AAAS) PMC |
| spellingShingle | Beste, Michael T. Pfaffle-Doyle, Nicole Prentice, Emily A. Lauffenburger, Douglas A. Morris, Stephanie N. Isaacson, Keith B. Griffith, Linda G. Molecular Network Analysis of Endometriosis Reveals a Role for c-Jun-Regulated Macrophage Activation |
| title | Molecular Network Analysis of Endometriosis Reveals a Role for c-Jun-Regulated Macrophage Activation |
| title_full | Molecular Network Analysis of Endometriosis Reveals a Role for c-Jun-Regulated Macrophage Activation |
| title_fullStr | Molecular Network Analysis of Endometriosis Reveals a Role for c-Jun-Regulated Macrophage Activation |
| title_full_unstemmed | Molecular Network Analysis of Endometriosis Reveals a Role for c-Jun-Regulated Macrophage Activation |
| title_short | Molecular Network Analysis of Endometriosis Reveals a Role for c-Jun-Regulated Macrophage Activation |
| title_sort | molecular network analysis of endometriosis reveals a role for c jun regulated macrophage activation |
| url | http://hdl.handle.net/1721.1/88950 https://orcid.org/0000-0002-1801-5548 |
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