Targeting Regulators of Outside-In Signaling in Ovarian Cancer
Abstract
Epithelial ovarian cancer is the most lethal of all gynecologic malignancies, with the majority of cases being diagnosed at an advanced stage. Current standard treatment of ovarian cancer, in both early and advanced stages, consists of complete cytoreductive surgery followed by chemotherapy, usually based on platinum/taxane combination. The initial response rate is high (70%-80%); but the majority of patients with advanced disease relapse within the first five years after diagnosis resulting in a cycle of repeated surgeries and additional rounds of chemotherapy. Recurrent ovarian cancer is not curable, due to the development of chemoresistance. Both recurrence and spread have been linked to a small population of ovarian cancer cells called ovarian cancer stem cells, which are resistant to approved chemotherapy agents for the treatment of recurrent ovarian cancer, such as platinum-based drugs and PARP inhibitors. The accumulation of ascites in the abdomen provides a favorable environment, enriched in growth factors and proteins that protects cancer stem cells during chemotherapy and promotes their growth. To date, treatment strategies designed to eliminate the genesis of ovarian cancer stem cells still remain a significant challenge. One main obstacle toward a successful treatment option for ovarian cancer remains the molecular identification of these tumorigenic cells. Our previous study demonstrated that tissue transglutaminase, an enzyme found to be active in ovarian tumors, protects cancer stem cells and stimulates their growth. We found that this enzyme is enriched at the membrane of cancer stem cells forming a complex with several receptors, such as integrins, which allow the stem cells to attach and grow in the peritoneal space. Additionally, we provided evidence that tissue transglutaminase binds to the cellular receptor frizzled 7 and that this interaction stimulates the oncogenic Wnt pathway in cancer stem cells. However, the exact mechanism by which tissue transglutaminase interaction with frizzled 7 promotes ovarian cancer progression and ovarian cancer stem cell survival after chemotherapy remains unknown. Our preliminary data discovered that the enzyme integrin-linked kinase, a signaling molecule recruited by beta 1 integrins upon binding to their extracellular-matrix ligands, such as fibronectin, is activated by the functional interaction between transglutaminase and frizzled 7, leading to Wnt aberrant signaling in ovarian cancer cells and cancer stem cells. In addition, our preliminary data demonstrate that integrin-linked kinase expression is upregulated in ovarian cancer cells and tumor specimens from ovarian cancer patients compared to the normal fallopian tube and ovarian epithelium, correlates with ovarian tumor grade, and promotes ovarian cancer stem cell survival and proliferation. Furthermore, ovarian cancer patients with higher integrin-linked kinase levels have worse survival rates. Integrin- linked kinase expression has already been linked to the cancerous behaviors of other cancer cells. Based on the previous premises, the hypothesis is that tissue transglutaminase engages the Wnt receptor frizzled 7 and activates Wnt signaling through integrin-linked kinase. This in turn promotes ovarian cancer progression and ovarian cancer stem cell self/renewal. Demonstration of this concept will provide the rationale to pursue new strategies to disrupt this mechanism with the goal of eliminating these tumorigenic cells. We propose to address the hypothesis by pursuing three objectives: 1) Define the integrin-linked kinase interaction with tissue transglutaminase and frizzled 7 in high-grade serous ovarian cancer cells and patient-derived organoids; 2) Determine whether integrin-linked kinase activation by tissues transglutaminase and frizzled 7 is altered in platinum-resistant OC models and tumors and required for maintaining the aggressive ovarian cancer stem cell phenotype. 3) Determine whether tissue
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310509
Entities
People
- Salvatore Condello
Organizations
- Indiana University
- United States Army