# Cell Growth Signaling in Cancer Development

> **NIH NIH R01** · WHITEHEAD INSTITUTE FOR BIOMEDICAL RES · 2021 · $463,125

## Abstract

Project Summary
 The mTOR pathway is a signaling system that regulates growth and metabolism in response to the
nutritional state of organisms. Increasing evidence shows that the pathway is commonly deregulated in
cancer, neurological disorders, and diabetes, and also modulates the aging process. The mTOR protein
kinase is the target of the drug rapamycin and the catalytic subunit of two multi-protein complexes,
mTOR Complex 1 (mTORC1) and 2 (mTORC2), that nucleate distinct branches of the pathway and
respond to different upstream signals. mTORC1 responds to a variety of stimuli, including diverse types
of growth factors, nutrients, and stresses, and regulates many anabolic and catabolic processes,
including protein, nucleotide, and lipid synthesis and autophagy, respectively. Recently, we discovered
that mTORC1 senses nutrients in part through the lysosome and identified a multi-pass lysosomal
membrane protein, SLC38A9, that is key for sensing the amino acid arginine. SLC38A9 turns out to be
much more interesting than we originally anticipated as not only does it signal to mTORC1 it also has
a major role in effluxing an essential amino acid out of the lysosome so it can be used in cytosolic
processes. In addition, using a new method we developed to profile the metabolite contents of
lysosomes, we made the surprising discovering that mTORC1 itself is a major regulator of the efflux of
most non-polar essential amino acids from lysosomes. Thus, mTORC1 is both downstream and
upstream of lysosomal function, indicating that it is part of a circuit that modulates and senses
lysosome function in response to growth signals. The broad goals of our work are to arrive at a
mechanistic understanding of how the lysosome signals to mTORC1 and in turn how mTORC1
regulates lysosome function. In addition, we have found that the mechanisms we are studying are
particularly important for the proliferation of pancreatic cancer cells and so we intend to test their roles
in the development of pancreatic tumors in mice.
 The specific aims of our proposed work are to: understand how the lysosomal membrane protein
SLC38A9 controls mTORC1 signaling (Aim 1); test the importance of SLC38A9 in the development of
pancreatic tumors (Aim 2); and understand how mTORC1 controls the efflux of lysosomal amino acids
(Aim 3). We will accomplish these goals with a multi-disciplinary approach that uses the tools of
biochemistry, molecular biology, and mouse engineering. Our results will substantially increase our
understanding of the clinically important mTORC1 pathway and test if SLC38A9 is a potential drug
target in pancreatic cancer.

## Key facts

- **NIH application ID:** 10065495
- **Project number:** 5R01CA129105-14
- **Recipient organization:** WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
- **Principal Investigator:** JONATHAN S. WEISSMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $463,125
- **Award type:** 5
- **Project period:** 2008-04-08 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10065495

## Citation

> US National Institutes of Health, RePORTER application 10065495, Cell Growth Signaling in Cancer Development (5R01CA129105-14). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10065495. Licensed CC0.

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