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.

Public Health 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA141078-02
Application #
8026619
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2010-04-01
Project End
2015-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
2
Fiscal Year
2011
Total Cost
$318,015
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Haria, Dhwani; Trinh, Bon Quy; Ko, Song Yi et al. (2015) The homeoprotein DLX4 stimulates NF-κB activation and CD44-mediated tumor-mesothelial cell interactions in ovarian cancer. Am J Pathol 185:2298-308
Trinh, Bon Q; Barengo, Nicolas; Kim, Sang Bae et al. (2015) The homeobox gene DLX4 regulates erythro-megakaryocytic differentiation by stimulating IL-1β and NF-κB signaling. J Cell Sci 128:3055-67
Trinh, Bon; Ko, Song Yi; Haria, Dhwani et al. (2015) The homeoprotein DLX4 controls inducible nitric oxide synthase-mediated angiogenesis in ovarian cancer. Mol Cancer 14:97
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
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; Naora, Honami (2014) Adaptation of ovarian cancer cells to the peritoneal environment: Multiple mechanisms of the developmental patterning gene HOXA9. Cancer Cell Microenviron 1:e379
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
Haria, Dhwani; Naora, Honami (2013) Homeobox Gene Deregulation: Impact on the Hallmarks of Cancer. Cancer Hallm 1:67-76
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
Ko, Song Yi; Barengo, Nicolas; Ladanyi, Andras et al. (2012) HOXA9 promotes ovarian cancer growth by stimulating cancer-associated fibroblasts. J Clin Invest 122:3603-17

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