ETS1 induction by the microenvironment promotes ovarian cancer metastasis through focal adhesion kinase

Metastatic colonization involves paracrine/juxtacrine interactions with the microenvironment inducing an adaptive response through transcriptional regulation. However, the identities of transcription factors (TFs) induced by the metastatic microenvironment in ovarian cancer (OC) and their mechanism...

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Bibliographic Details
Published in:Cancer letters 2018-02, Vol.414, p.190-204
Main Authors: Tomar, Sunil, Plotnik, Joshua P., Haley, James, Scantland, Joshua, Dasari, Subramanyam, Sheikh, Zahir, Emerson, Robert, Lenz, Dean, Hollenhorst, Peter C., Mitra, Anirban K.
Format: Article
Language:English
Subjects:
Cell adhesion & migration
Cell culture
Colonization
Environment
ETS protein
Ets-1 protein
ETS1
FAK
Focal adhesion kinase
Gene regulation
Kinases
MAP kinase
Metastases
Metastasis
Microenvironment
Omentum
Ovarian cancer
Ovarian carcinoma
Paracrine signalling
Ribonucleic acid
RNA
Transcription factors
Tumors
Xenografts
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Summary:Metastatic colonization involves paracrine/juxtacrine interactions with the microenvironment inducing an adaptive response through transcriptional regulation. However, the identities of transcription factors (TFs) induced by the metastatic microenvironment in ovarian cancer (OC) and their mechanism of action is poorly understood. Using an organotypic 3D culture model recapitulating the early events of metastasis, we identified ETS1 as the most upregulated member of the ETS family of TFs in metastasizing OC cells as they interacted with the microenvironment. ETS1 was regulated by p44/42 MAP kinase signaling activated in the OC cells interacting with mesothelial cells at the metastatic site. Human OC tumors had increased expression of ETS1, which predicted poor prognosis. ETS1 regulated OC metastasis both in vitro and in mouse xenografts. A combination of ChIP-seq and RNA-seq analysis and functional rescue experiments revealed FAK as the key transcriptional target and downstream effector of ETS1. Taken together, our results indicate that ETS1 is an essential transcription factor induced in OC cells by the microenvironment, which promotes metastatic colonization though the transcriptional upregulation of its target FAK. •ETS1 is upregulated in ovarian cancer cells by the metastatic microenvironment.•Induction of p44/42 MAP kinase signaling increases ETS1 expression.•ETS1 promotes ovarian cancer metastatic colonization.•PTK2 (FAK) is a key transcriptional target of ETS1 that mediates its functions.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2017.11.012