Format

Send to

Choose Destination
Cancer Lett. 2018 Feb 1;414:190-204. doi: 10.1016/j.canlet.2017.11.012. Epub 2017 Nov 22.

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

Author information

1
Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN, United States.
2
Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN, United States.
3
Urology, IU Health Southern Indiana Physicians, Bloomington, IN, United States.
4
Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN, United States; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, United States; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States.
5
Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN, United States; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, United States; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States. Electronic address: anmitra@indiana.edu.

Abstract

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.

KEYWORDS:

ETS1; FAK; Metastasis; Microenvironment; Omentum; Ovarian cancer

PMID:
29174800
DOI:
10.1016/j.canlet.2017.11.012
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center