Ovarian cancer (OvCa) is the most fatal gynecologic cancer with a low (<27%) 5-year survival rate. Survival of women with OvCa has not changed appreciably in over 30 years and most women diagnosed will die of painful complications that arise as a result of widely disseminated intraperitoneal (IP) metastasis. Epidemiologic data indicate that age is a significant risk factor for OvCa incidence; however disease progression in the aged host has not been examined experimentally. In the previous funding period we developed a suite of new in vitro, ex vivo, and in vivo model systems and imaging modalities with which to examine the mechanistic link between host age and ovarian cancer metastatic success. Using these models, our preliminary data show age-related alterations in peritoneal mesothelial cells (MC) and sub-mesothelial collagen together with enhanced tumor burden in aged relative to young mice and suggest that Wnt5a can function as a mediator of tumor:host cross-talk in the peritoneal cavity. Experiments in the current project will address the hypothesis that host ageing induces changes in peritoneal structure and function that influence tumor cell adhesion, matrix anchoring, and subsequent metastatic success. To address this hypothesis, Aim 1 will examine age-induced changes in peritoneal MCs, the response of aged MCs to compression and strain, and the resulting impact on MC receptivity to metastatic implantation.
Aim2 will focus on ageing of the sub-MC collagen matrix, evaluate age-induced matrix crosslinking and biophysical properties, and the ultimate effect on metastatic anchoring.
Aim3 will investigate Wnt5a as a mediator of tumor:host cross-talk in the ageing peritoneal cavity. Successful completion of these aims will provide unparalleled insight into ageing and IP metastasis. As the high mortality of OvCa is directly attributable to IP metastasis, innovative approaches that integrate data from both tumor and host will identify critical determinants of metastatic success for future targeted intervention.
Age is a significant risk factor for ovarian cancer (OvCa), as the majority of women are diagnosed over age 63. At the time of diagnosis, most women already have metastatic disease spread throughout the abdomen; however the impact of ageing peritoneal tissues on metastatic success has not been evaluated. This project integrates mechanistic biochemistry with tissue explants and mouse tumor models to understand the role of host ageing in OvCa metastasis. The goal is to identify specific molecules, structures and events that may be new therapeutic targets.
|Bailey, Karen A; Klymenko, Yuliya; Feist, Peter E et al. (2017) Chemical Analysis of Morphological Changes in Lysophosphatidic Acid-Treated Ovarian Cancer Cells. Sci Rep 7:15295|
|Klymenko, Y; Kim, O; Loughran, E et al. (2017) Cadherin composition and multicellular aggregate invasion in organotypic models of epithelial ovarian cancer intraperitoneal metastasis. Oncogene 36:5840-5851|
|Yang, Jing; Kasberg, William C; Celo, Angela et al. (2017) Post-translational modification of the membrane type 1 matrix metalloproteinase (MT1-MMP) cytoplasmic tail impacts ovarian cancer multicellular aggregate dynamics. J Biol Chem 292:13111-13121|
|Klymenko, Yuliya; Johnson, Jeffrey; Bos, Brandi et al. (2017) Heterogeneous Cadherin Expression and Multicellular Aggregate Dynamics in Ovarian Cancer Dissemination. Neoplasia 19:549-563|
|Klymenko, Yuliya; Kim, Oleg; Stack, M Sharon (2017) Complex Determinants of Epithelial: Mesenchymal Phenotypic Plasticity in Ovarian Cancer. Cancers (Basel) 9:|
|Bruney, Lana; Liu, Yueying; Grisoli, Anne et al. (2016) Integrin-linked kinase activity modulates the pro-metastatic behavior of ovarian cancer cells. Oncotarget 7:21968-81|
|Asem, Marwa S; Buechler, Steven; Wates, Rebecca Burkhalter et al. (2016) Wnt5a Signaling in Cancer. Cancers (Basel) 8:|
|Mitra, Anirban K; Davis, David A; Tomar, Sunil et al. (2015) In vivo tumor growth of high-grade serous ovarian cancer cell lines. Gynecol Oncol 138:372-7|
|Burkhalter, Rebecca J; Westfall, Suzanne D; Liu, Yueying et al. (2015) Lysophosphatidic Acid Initiates Epithelial to Mesenchymal Transition and Induces ?-Catenin-mediated Transcription in Epithelial Ovarian Carcinoma. J Biol Chem 290:22143-54|
|Liu, Yueying; Metzinger, Matthew N; Lewellen, Kyle A et al. (2015) Obesity Contributes to Ovarian Cancer Metastatic Success through Increased Lipogenesis, Enhanced Vascularity, and Decreased Infiltration of M1 Macrophages. Cancer Res 75:5046-57|
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