Data from A Collagen-Remodeling Gene Signature Regulated by TGF-β Signaling Is Associated with Metastasis and Poor Survival in Serous Ovarian Cancer

Abstract

<div>Abstract<p><b>Purpose:</b> To elucidate molecular pathways contributing to metastatic cancer progression and poor clinical outcome in serous ovarian cancer.</p><p><b>Experimental Design:</b> 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 <i>in situ</i> hybridization. Alterations in gene expression by TGF-β1 and functional consequences of loss of <i>COL11A1</i> were evaluated using pharmacologic and knockdown approaches, respectively.</p><p><b>Results:</b> We identified and validated a 10-gene signature (<i>AEBP1</i>, <i>COL11A1</i>, <i>COL5A1</i>, <i>COL6A2</i>, <i>LOX</i>, <i>POSTN</i>, <i>SNAI2</i>, <i>THBS2</i>, <i>TIMP3</i>, and <i>VCAN</i>) 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 <i>COL11A1</i>, one of the signature genes, continuously increase during ovarian cancer disease progression, with the highest expression in recurrent metastases. Knockdown of <i>COL11A1</i> decreases <i>in vitro</i> cell migration, invasion, and tumor progression in mice.</p><p><b>Conclusion:</b> 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. <i>Clin Cancer Res; 20(3); 711–23. ©2013 AACR</i>.</p></div>