Exploration of the immunosuppressive function of RBMS3/PRRX1 axis in TNBC
NIH
WAYNE STATE UNIVERSITY
Abstract The epithelial to mesenchymal transition (EMT), a developmental process related to tissue repair and pathological processes, has been found to occur in the progression of carcinomas to invasive and metastatic disease. Accumulated evidence suggests the EMT could contribute to the immunosuppressive function of cancer cells. However, the underlying molecular mechanism linking EMT and immunosuppressive function in cancer remain largely unknown. To tackle this problem, our research group developed an integrative transcriptomic approach to combine expression profiling of breast cancer cell lines and several mammary epithelial cell EMT models. This screen identified RNA-binding motif single-stranded interacting protein 3 (RBMS3) as being significantly and reproducibly associated with EMT. We further showed that RBMS3 stabilized a group of EMT-related genes, including PRRX1. Functional analysis demonstrated the RBMS3/PRRX1 axis is responsible for maintaining mesenchymal status and motility properties of breast cancer cells, as well as controlling a group of pro- inflammatory cytokines. More importantly, knockdown of RBMS3 in TNBC MDA-MB231 cells results in a significant delay of tumorigenesis in vivo, which is not observed in vitro. These results indicate RBMS3 mediates breast cancer progression, potentially by simultaneously increasing invasive potential and promoting an immunosuppressed tumor microenvironment. In this study, we propose to investigate the effect of RBMS3/PRRX1 axis on immunosuppression and breast cancer progression in immunocompetent animal models and explore the potential impact of targeting RBMS3/PRRX1 axis in facilitating immunotherapy in TNBC models. We expect the proposed studies to be completed within two years, with two critical outcomes: 1) revealing the role of RBMS3/PRRX1 axis in driving TNBC progression through detailed analysis of the alterations of immune- microenvironment; 2) proof-of-concept evidence that targeting RBMS3/PRRX1 axis will facilitate immunotherapy for TNBC treatment. These results will lay a solid foundation for further development of specific targeting RBMS3/PRRX1axis for treatment of TNBC. By achieving these goals, we will be able to address the following overarching challenges: 1) identify why some breast cancers become life-threatening metastases; and 2) eliminate or reduce the mortality associated with metastatic breast cancer. Project Narrative In this proposal, we will employ complementary molecular, cellular, genetics, and state-of-the-arts next-generation sequencing techniques, as well as various mouse models, to investigate the function of RBMS3/PRRX1 axis in regulating immunosuppressive effect and response to immunotherapy for TNBC. The results of this study will not only provide insight into the mechanism of TNBC progression, but also lay the foundation for establishing the RBMS3/PRRX1 axis as a therapeutic target for TNBC treatment.
Non-SBIR/STTR