Wednesday, April 24, 2024
4/24/2024
ABSTRACT Many RAS-transformed aggressive cancer cells are able to escape cytotoxic chemotherapy and survive in near-starvation conditions. One adaptation making them hard to kill is their ability to scavenge extracellular proteins and recycle the cellular components using autophagy, both of which are then digested in lysosomes to recover free amino acids. The process of scavenging and internalization is known as macropinocytosis, and cancer cells aquire mutations to upregulate it when faced with nutrient-poor conditions. To fight such cancers, researchers are currently targeting the macropinocytosis machinery; however, because this process is not very well studied, and likely involves hundreds of proteins with redundant functions, such therapy might prove challenging to exectute without involving multiple drugs. We propose a better way of targeting nutrient-scavenging cancers by focusing on a downstream process of releasing digested nutrients from lysosomes to cytosol. The Sabatini Lab showed that the release of digested amino acids from lysosomes is orchestrated by the mTORC1 pathway, and specifically by SLC38A9. This lysosomal membrane protein senses the rising levels of digested amino acids in lysosomes by directly binding arginine. Our lab found that this sensing is coupled to activation of the transporter function, and results in the efflux of essential non-polar amino-acids, such as leucine, from lysosomes to cytosol. Importantly, RAS-transformed pancreatic cancer cells that feed on extracellular protein were unable to efficiently form tumors in the absence of SLC38A9. These results present a novel therapeutic idea of targeting a metabolic vulnerability in cancers transformed by oncogenic RAS signaling. In this five-year project we will elucidate the molecular mechanism of releasing digested amino acids from lysosomes to cytosol via SLC38A9, and therefore provide a rational approach to drug discovery. In parallel to that, we will screen for small molecules that specifically bind to SLC38A9, and develop them into chemical probes that modulate its transport activity. Impaired efflux function of SLC38A9 will lead to entrapment of macropinocytosis-derived amino-acids within the lysosomes, and our expectation is that this treatment will impair the growth of RAS-mutant and other tumors addicted to protein scavenging, while sparing normal cells that lack this requirement. Over the first two years of the mentored phase, I will be based at the Whitehead Institute, where I will learn cell signaling and metabolomics approaches from the experts in the field. I will also venture into a completely new research area to me, chemical biology, working with experts at the Broad Institute. After the completion of my K99 training, my aspiration is to lead a laboratory that combines cell signaling, structural biology, and chemical biology to study membrane transporters and their role in cancer metabolism. In parallel to understanding basic biology, I want my lab to develop specific small-molecule modulators that adjust transport activities of those proteins, facilitating further research in the field, and in long term – new medicines.
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