# The Macropinosome: Uncovering the Molecular Anatomy of an Oncogene-driven Organelle

> **NIH NIH R21** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2021 · $227,906

## Abstract

PROJECT SUMMARY
As an integral aspect of the metabolic reprogramming that occurs in cancer, oncogenic KRAS mutations drive
the stimulation of macropinocytosis, a type of endocytosis that mediates nonselective fluid-phase uptake. Using
KRAS-driven models of pancreatic ductal adenocarcinoma (PDAC), we were the first to demonstrate that
macropinocytosis functions in tumor cells as a nutrient acquisition pathway. Macropinocytosis triggers the
internalization of extracellular proteins via discrete endocytic vesicles called macropinosomes. The incoming
protein cargo is targeted for lysosome-dependent degradation, causing the intracellular release of amino acids.
These protein-derived amino acids support metabolic fitness by contributing to the intracellular amino acid pools,
as well as to the biosynthesis of central carbon metabolites. In this way, macropinocytosis represents a novel
amino acid supply route that tumor cells use to survive the nutrient-poor conditions of the tumor
microenvironment. While the tenets of the signal transduction events that drive macropinocytosis in cancer have
emerged, a detailed picture of the macropinosome itself is not yet available. With the aid of nanotechnology, we
have developed methodology to isolate a pure fraction of macropinosomes from PDAC cells. Having the
capability to purify macropinosomes, we are now uniquely positioned to benefit from largescale proteomics that
can provide a broad picture of this important organelle. By elucidating the molecular anatomy of KRAS-driven
macropinosomes, we will gain further insight into the regulation and function of macropinocytosis in cancer.
Moreover, having a clearer picture of the macropinosome will make us better positioned to exploit this pathway
therapeutically and deliver breakthroughs to patients.

## Key facts

- **NIH application ID:** 10153719
- **Project number:** 5R21CA243701-02
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** COSIMO COMMISSO
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $227,906
- **Award type:** 5
- **Project period:** 2020-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10153719

## Citation

> US National Institutes of Health, RePORTER application 10153719, The Macropinosome: Uncovering the Molecular Anatomy of an Oncogene-driven Organelle (5R21CA243701-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10153719. Licensed CC0.

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