UPTAKE · How do cells absorb nutrients: Spatially resolving nutrient uptake using intestinal cells as a paradigm

Cells need a constant supply of nutrients to maintain homeostasis, integrity and identity. In multicellular organisms, cells of different types tightly control this chemical exchange with their environment depending on metabolic requirements. While intracellular metabolic and nutrient-sensing pathways are widely studied, our understanding of how cells regulate their nutrient uptake in the first place remains largely unexplored. Nutrient uptake occurs at the cellular membranes via transporter proteins. In this context, I recently identified a case where a solute carrier (SLC) transporter controls intestinal cancer cell growth and metastasis to distant organs. Considering the intestine is the major nexus for almost all nutrient uptake, we do not yet know the functional impact of transporters on intestinal stem cells and in pathological conditions such as cancer, with a lack of relevant in vivo experimental model systems limiting further investigation. Applying my expertise at the intersection of metabolism, stem cell and cancer biology, I propose using intestine as a paradigm to create models and methods to advance understanding of nutrient UPTAKE via SLCs in intestinal cells in vivo (UPTAKE), addressing the present discovery-limiting technical shortfall. I will: i) use advanced genetically engineered mouse models and spatial metabolic imaging tools to map the metabolism of intestinal stem cells and cancer initiating cells; ii) create new state-of-the-art, scalable genetic models to comprehensively study the role of SLCs in cancer initiation and progression; and iii) finally, mechanistically characterize the identified SLCs in vivo using mouse models and spatial multi-omics methods. Through UPTAKE, I will answer fundamental questions on how intestinal stem and cancer cells meet their specialized nutrient needs while creating broadly applicable genetic tools and models to power further research into SLCs that contribute to metabolic rewiring in many other cancers.