A collagen-remodeling gene signature regulated by TGF-β signaling is associated with metastasis and poor survival in serous ovarian cancer.
OBJECTIVE
To elucidate molecular pathways contributing to metastatic cancer progression and poor clinical outcome in serous ovarian cancer.


METHODS
Poor survival signatures from three different serous ovarian cancer datasets were compared and a common set of genes was identified. The predictive value of this gene signature was validated in independent datasets. The expression of the signature genes was evaluated in primary, metastatic, and/or recurrent cancers using quantitative PCR and in situ hybridization. Alterations in gene expression by TGF-β1 and functional consequences of loss of COL11A1 were evaluated using pharmacologic and knockdown approaches, respectively.


RESULTS
We identified and validated a 10-gene signature (AEBP1, COL11A1, COL5A1, COL6A2, LOX, POSTN, SNAI2, THBS2, TIMP3, and VCAN) that is associated with poor overall survival (OS) in patients with high-grade serous ovarian cancer. The signature genes encode extracellular matrix proteins involved in collagen remodeling. Expression of the signature genes is regulated by TGF-β1 signaling and is enriched in metastases in comparison with primary ovarian tumors. We demonstrate that levels of COL11A1, one of the signature genes, continuously increase during ovarian cancer disease progression, with the highest expression in recurrent metastases. Knockdown of COL11A1 decreases in vitro cell migration, invasion, and tumor progression in mice.


CONCLUSIONS
Our findings suggest that collagen-remodeling genes regulated by TGF-β1 signaling promote metastasis and contribute to poor OS in patients with serous ovarian cancer. Our 10-gene signature has both predictive value and biologic relevance and thus may be useful as a therapeutic target.
Authors' Affiliations: Women's Cancer Program, Department of Medicine, Biostatistics and Bioinformatics Research Center, Samuel Oschin Comprehensive Cancer Institute; Department of Pathology and Laboratory Medicine; Graduate Program in Biomedical Sciences and Translational Medicine, Cedars-Sinai Medical Center; Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles; and John Wayne Cancer Institute, Saint John's Hospital, Santa Monica, California.
Dong-Joo
DJ
Cheon
Yunguang
Y
Tong
Myung-Shin
MS
Sim
Judy
J
Dering
Dror
D
Berel
Xiaojiang
X
Cui
Jenny
J
Lester
Jessica A
JA
Beach
Mourad
M
Tighiouart
Ann E
AE
Walts
Beth Y
BY
Karlan
Sandra
S
Orsulic
D000818:Animals; D003094:Collagen / Q000235:genetics* / Q000378:metabolism; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D053208:Kaplan-Meier Estimate; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism
D016212:Transforming Growth Factor beta; D003094:Collagen