Deciphering the TRAIL pathway in Ovarian Cancer

The research of our lab focuses on the pathogenesis of human epithelial ovarian cancer. We want to develop novel diagnostic and therapeutic tools based on a better understanding of the molecular mechanisms behind this disease. In a previous FWF project we have identified a major role for the tumor necrosis factor (TNF)-related apoptosis- inducing ligand (TRAIL) and its functional receptors in ovarian cancer. We could demonstrate, that a high percentage of cases shows a deregulation of the TRAIL induced apoptotic pathway, and that this may be caused by epigenetic downregulation of the TRAIL receptor 1 (DR4) and/or overexpression of an apoptosis inhibiting protein (c-FLIP). Moreover, we observed that ovarian cancers have high TRAIL expression in the tumor microenvironment and that high expression of TRAIL is associated with prolonged survival. Consequently, we want to investigate these important observations in more detail as well as in the broader context of tumor surveillance. Most human tumors eventually continue to grow independently of spontaneous or therapy induced immune responses, a process described as escape from tumor surveillance. There is ample evidence that this happens due to the ability of a fraction of cancer cells to continuously evade potentially effective immune recognition and destruction. Mechanisms include increased induction of thresholds for apoptosis, loss of antigen processing and presentation capabilities of tumor cells, antigenic-loss variants, enhanced negative signaling and decreased activation of NK-cells as well as antigen specific T-cells. All these various processes may act simultaneously making the overall tumor-host interaction extremely complex. In addition, cancer itself also suppresses host immunity by multiple mechanisms. We will set a spotlight on the development of apoptosis resistance in the course of ovarian carcinogenesis, as potential interface between immune system and cancer development. In the proposed experiments we will examine the importance of the TRAIL pathway in spontaneous metastasis of ovarian cancer. We will apply new techniques for co-culture of natural killer cells with ovarian cancer cells, and establish a syngeneic ovarian cancer model in immunocompetent mice, in order to decipher the role of TRAIL in host protection from ovarian tumor metastasis. These new techniques will enable us to provide a novel strategy to describe the critical role of TRAIL in innate immune surveillance of ovarian cancer. The results will have substantial implications for both, the development of spontaneous immunity of cancer cells - and consequently the pathogenesis of ovarian cancer in general - as well as various treatment approaches including immunotherapy, emerging therapeutic options like targeted and deacetylation therapies, and systemic chemotherapy, which continues to represent the standard treatment of advanced ovarian cancer.

The research of our lab focuses on the pathogenesis of human epithelial ovarian cancer. We want to develop novel diagnostic and therapeutic tools based on a better understanding of the molecular mechanisms behind this disease. In a previous FWF project we have identified a major role for the tumor necrosis factor (TNF)-related apoptosis- inducing ligand (TRAIL) and its functional receptors in ovarian cancer. We could demonstrate, that a high percentage of cases shows a deregulation of the TRAIL induced apoptotic pathway, and that this may be caused by epigenetic downregulation of the TRAIL receptor 1 (DR4) and/or overexpression of an apoptosis inhibiting protein (c-FLIP). Moreover, we observed that ovarian cancers have high TRAIL expression in the tumor microenvironment and that high expression of TRAIL is associated with prolonged survival. Consequently, we want to investigate these important observations in more detail as well as in the broader context of tumor surveillance. Most human tumors eventually continue to grow independently of spontaneous or therapy induced immune responses, a process described as escape from tumor surveillance. There is ample evidence that this happens due to the ability of a fraction of cancer cells to continuously evade potentially effective immune recognition and destruction. Mechanisms include increased induction of thresholds for apoptosis, loss of antigen processing and presentation capabilities of tumor cells, antigenic-loss variants, enhanced negative signaling and decreased activation of NK-cells as well as antigen specific T-cells. All these various processes may act simultaneously making the overall tumor-host interaction extremely complex. In addition, cancer itself also suppresses host immunity by multiple mechanisms. We will set a spotlight on the development of apoptosis resistance in the course of ovarian carcinogenesis, as potential interface between immune system and cancer development. In the proposed experiments we will examine the importance of the TRAIL pathway in spontaneous metastasis of ovarian cancer. We will apply new techniques for co-culture of natural killer cells with ovarian cancer cells, and establish a syngeneic ovarian cancer model in immunocompetent mice, in order to decipher the role of TRAIL in host protection from ovarian tumor metastasis. These new techniques will enable us to provide a novel strategy to describe the critical role of TRAIL in innate immune surveillance of ovarian cancer. The results will have substantial implications for both, the development of spontaneous immunity of cancer cells - and consequently the pathogenesis of ovarian cancer in general - as well as various treatment approaches including immunotherapy, emerging therapeutic options like targeted and deacetylation therapies, and systemic chemotherapy, which continues to represent the standard treatment of advanced ovarian cancer.