Research Projects

Rationale: Brain metastasis (BM) present a significant clinical challenge, characterized by high mortality rates and therapy resistance. Another challenge with BM is the varying metastatic fitness, as some metastatic cells grow rapidly and detected with the primary tumor, while others stay dormant for long periods and facilitate late relapse. Why this disparity in the metastatic fitness? Is this linked to self-autonomy or nutrient dependency phenomena? If so, dormant cells may depend heavily the brain microenvironment (BME), whereas aggressive metastatic cells might exhibit greater metabolic independence and will be less dependent on BME. Thus, understanding the nutrient dependency and metabolic state is key. Since Solute Carrier (SLC) transporters are central to nutrient uptake and metabolic regulation, this project aims to decode their role in driving differential metastatic fitness by investigating their contributions to nutrient uptake and metabolic rewiring. Scientific Objectives: The primary objective of this study is to investigate the differential expression of SLC transporters in slow-cycling (BrM-Slow) and aggressive (BrM-Fast) BM cells generated using unique mice models. Exploiting these models and cell lines, we will identify the essential nutrients and metabolic substrates each cell type acquires through SLC transporters from the BME. Next, we will understand how these transporters acquired nutrients influence mitochondrial dynamics and metabolic rewiring, contributing to the differential growth of BM cells. Finally, we will target SLC transporters or mitochondrial dynamics by genetic manipulation or inhibitor-based approaches. Key Experiments: To identify key upregulated SLC transporters in BrM-Slow and BrM-Fast cells we will conduct bioinformatics analysis of available RNA-seq data of BM cells and validate the altered expression of SLCs using qPCR and Western blot. Next, we will perform steady-state metabolomics and 13C isotope tracing followed by fluxomics in co-culture with brain-resident cells to map the nutrient source, uptake mechanism and associated altered metabolic profiles. To investigate the functional role of SLCs, we will use inducible CRISPRi or shRNA systems to knock down key SLCs and assess their impact on nutrient uptake, mitochondrial dynamics, and metabolic rewiring. Finally, using in vivo models we will evaluate the therapeutic potential and validate preclinical findings with patient samples. Significance: This project has the potential to significantly enhance our understanding of BM by elucidating how SLCs contribute to nutrient uptake, mitochondrial dynamics, and metabolic rewiring and influences the differential metastatic fitness. The findings of this project have potential to reveal novel biomarkers for BM, also could offer insights for improved diagnostic tools and better monitoring strategies. Additionally, outcome from this study could generate potential targets to treat BM and enhance patient outcomes.