Alterations of the MEK/ERK, BMP, and Wnt/β-catenin pathways detected in the blood of individuals with lymphatic malformations.

Lymphatic malformation (LM) is a developmental anomaly of the lymphatic system that may lead to disfigurement, organ dysfunction and recurrent infection. Though several treatment modalities exist, pharmacotherapy is often associated with side effects and recurrence is common following surgical inter...

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Main Authors: Taehan Kim, Elidia Tafoya, Malcolm P Chelliah, Ramrada Lekwuttikarn, Jiang Li, Kavita Y Sarin, Joyce Teng
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2019-01-01
Series:PLoS ONE
Online Access:https://doi.org/10.1371/journal.pone.0213872
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spelling doaj-d9bbcf8974bd4b408d70725cacae50e72021-03-03T20:45:44ZengPublic Library of Science (PLoS)PLoS ONE1932-62032019-01-01144e021387210.1371/journal.pone.0213872Alterations of the MEK/ERK, BMP, and Wnt/β-catenin pathways detected in the blood of individuals with lymphatic malformations.Taehan KimElidia TafoyaMalcolm P ChelliahRamrada LekwuttikarnJiang LiKavita Y SarinJoyce TengLymphatic malformation (LM) is a developmental anomaly of the lymphatic system that may lead to disfigurement, organ dysfunction and recurrent infection. Though several treatment modalities exist, pharmacotherapy is often associated with side effects and recurrence is common following surgical interventions. Moreover, despite the recent discovery of PIK3CA mutations in lymphatic endothelial cells of LM patients, the full spectrum of molecular pathways involved in LM pathogenesis is poorly understood. Here, we performed RNA sequencing on blood samples obtained from ten LM patients and nine healthy subjects and found 421 differentially expressed genes that stratify LM subjects from healthy controls. Using this LM gene signature, we identified novel pathway alterations in LM, such as oxidative phosphorylation, MEK/ERK, bone morphogenetic protein (BMP), and Wnt/β-catenin pathways, in addition to confirming the known alterations in cell cycle and the PI3K/AKT pathway. Furthermore, we performed computational drug repositioning analysis to predict existing therapies (e.g. sirolimus) and novel classes of drugs for LM. These findings deepen our understanding of LM pathogenesis and may facilitate non-invasive diagnosis, pathway analysis and therapeutic development.https://doi.org/10.1371/journal.pone.0213872
collection DOAJ
language English
format Article
sources DOAJ
author Taehan Kim
Elidia Tafoya
Malcolm P Chelliah
Ramrada Lekwuttikarn
Jiang Li
Kavita Y Sarin
Joyce Teng
spellingShingle Taehan Kim
Elidia Tafoya
Malcolm P Chelliah
Ramrada Lekwuttikarn
Jiang Li
Kavita Y Sarin
Joyce Teng
Alterations of the MEK/ERK, BMP, and Wnt/β-catenin pathways detected in the blood of individuals with lymphatic malformations.
PLoS ONE
author_facet Taehan Kim
Elidia Tafoya
Malcolm P Chelliah
Ramrada Lekwuttikarn
Jiang Li
Kavita Y Sarin
Joyce Teng
author_sort Taehan Kim
title Alterations of the MEK/ERK, BMP, and Wnt/β-catenin pathways detected in the blood of individuals with lymphatic malformations.
title_short Alterations of the MEK/ERK, BMP, and Wnt/β-catenin pathways detected in the blood of individuals with lymphatic malformations.
title_full Alterations of the MEK/ERK, BMP, and Wnt/β-catenin pathways detected in the blood of individuals with lymphatic malformations.
title_fullStr Alterations of the MEK/ERK, BMP, and Wnt/β-catenin pathways detected in the blood of individuals with lymphatic malformations.
title_full_unstemmed Alterations of the MEK/ERK, BMP, and Wnt/β-catenin pathways detected in the blood of individuals with lymphatic malformations.
title_sort alterations of the mek/erk, bmp, and wnt/β-catenin pathways detected in the blood of individuals with lymphatic malformations.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2019-01-01
description Lymphatic malformation (LM) is a developmental anomaly of the lymphatic system that may lead to disfigurement, organ dysfunction and recurrent infection. Though several treatment modalities exist, pharmacotherapy is often associated with side effects and recurrence is common following surgical interventions. Moreover, despite the recent discovery of PIK3CA mutations in lymphatic endothelial cells of LM patients, the full spectrum of molecular pathways involved in LM pathogenesis is poorly understood. Here, we performed RNA sequencing on blood samples obtained from ten LM patients and nine healthy subjects and found 421 differentially expressed genes that stratify LM subjects from healthy controls. Using this LM gene signature, we identified novel pathway alterations in LM, such as oxidative phosphorylation, MEK/ERK, bone morphogenetic protein (BMP), and Wnt/β-catenin pathways, in addition to confirming the known alterations in cell cycle and the PI3K/AKT pathway. Furthermore, we performed computational drug repositioning analysis to predict existing therapies (e.g. sirolimus) and novel classes of drugs for LM. These findings deepen our understanding of LM pathogenesis and may facilitate non-invasive diagnosis, pathway analysis and therapeutic development.
url https://doi.org/10.1371/journal.pone.0213872
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