PDF, English Restricted access: Repository staff only until 20 July 2024. Login+Download (5MB) | Terms of use

Abstract

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype with limited targeted therapy options. Stromal and immune cells densely populate the tumor microenvironment (TME) and are central players in the metabolic reprogramming of cancer. Therefore, elucidating the key metabolic vulnerabilities in the TME, offers new therapeutic perspectives for TNBC. In this study, I introduce the use of Dual Ribosome Profiling (DualRP) as a novel approach for uncovering cell-type specific metabolic limitations in the naïve TME. Firstly, to establish DualRP, systems of ribosomal fluorescent tagging in TNBC cells and fibroblasts were developed and validated. Secondly, DualRP revealed deregulated signaling mechanisms and metabolic interactions in both cell populations interacting simultaneously, which were further validated in vitro and in vivo. Thirdly, DualRP transgenic mouse models confirmed the metabolic vulnerabilities of T cells in TNBC tumors. Lastly, to exploit the metabolic vulnerabilities of TNBC for therapy, the combination of checkpoint inhibition and dietary restriction was applied in vivo. Collectively, my project presents a robust approach to study metabolic vulnerabilities in multiple compartments of the TME simultaneously.