Mechanistic insights into lysosomal nutrient efflux in cancer - 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.
