Seventy percent of women who are diagnosed with epithelial ovarian cancer (EOC) present with advanced- stage disease and are rarely cured by surgery and conventional chemotherapy. Understanding the molecular pathogenesis of EOC is essential to identify more accurate markers to improve early detection, and cancer- specific molecular alterations against which new-generation targeted therapies can be developed. Our goal is to identify novel molecular focal points that control the multiple pathways that drive the pathogenesis of EOC. Many pathways that drive tumor pathogenesis are aberrations of processes that control normal embryonic development. We have found that the homeobox patterning gene DLX4 is not expressed in normal ovary and benign cysts, whereas its expression in malignant EOC is strongly associated with ascites, high tumor grade and advanced disease stage. Our studies of xenograft models demonstrated that DLX4 promotes EOC growth, dissemination, vascularization and ascites. We hypothesize that DLX4 is a molecular focal point that promotes the pathogenesis of EOC by inducing a pro-angiogenic, metastatic program. The goal of this proposal is to determine the mechanism by which DLX4 acts as a molecular switch to induce expression of effectors that drive EOC pathogenesis.
Our specific aims are to determine: 1) the regulatory level at which DLX4 controls expression of key pro-angiogenic, metastatic factors 2) a novel regulatory mechanism by which DLX4 re-programs gene expression 3) the clinical significance and prognostic relevance of this re-programming mechanism In its tasks and implications, this proposal addresses the essential need for basic research of the biology of EOC. Moreover, in investigating novel regulatory mechanisms of a patterning gene in tumor pathogenesis, the study provides critical insight into how cancer is intimately related to embryonic development.
/RELEVANCE This proposal is directed to the study of epithelial ovarian cancer, a poorly-understood disease that is characterized by aggressive dissemination and is the fifth leading cause of female cancer death. We will study novel mechanisms by which deregulation of an embryonic patterning gene in epithelial ovarian cancer promotes tumor growth, dissemination, angiogenesis and ascites.
|Usui, Akihiro; Ko, Song Yi; Barengo, Nicolas et al. (2014) P-cadherin promotes ovarian cancer dissemination through tumor cell aggregation and tumor-peritoneum interactions. Mol Cancer Res 12:504-13|
|Ko, Song Yi; Ladanyi, Andras; Lengyel, Ernst et al. (2014) Expression of the homeobox gene HOXA9 in ovarian cancer induces peritoneal macrophages to acquire an M2 tumor-promoting phenotype. Am J Pathol 184:271-81|
|Ko, Song Yi; Naora, Honami (2014) HOXA9 promotes homotypic and heterotypic cell interactions that facilitate ovarian cancer dissemination via its induction of P-cadherin. Mol Cancer 13:170|
|Trinh, Bon Q; Ko, Song Yi; Barengo, Nicolas et al. (2013) Dual functions of the homeoprotein DLX4 in modulating responsiveness of tumor cells to topoisomerase II-targeting drugs. Cancer Res 73:1000-10|
|Trinh, B Q; Barengo, N; Naora, H (2011) Homeodomain protein DLX4 counteracts key transcriptional control mechanisms of the TGF-ýý cytostatic program and blocks the antiproliferative effect of TGF-ýý. Oncogene 30:2718-29|