# Molecular Basis and Regulatory Mechanisms of Exosome Secretion

> **NIH NIH R35** · UNIVERSITY OF PENNSYLVANIA · 2021 · $507,321

## Abstract

ABSTRACT
Exosomes are lipid-encapsulated small vesicles secreted by cells to the extracellular milieu, and are recently
recognized as a novel and highly effective means of cell-cell communication. Exosomes carry bioactive molecules
such as signaling proteins and microRNAs that potently affect the behavior and function of their recipient cells.
Studies in recent years have implicated the exosomes in a wide range of pathophysiological processes such as
organogenesis, viral propagation, tumor metastasis and immune suppression. Despite the great interest in
exosomes in various fields, the basic cell biological understanding of exosomes is disproportionally lacking. The
biogenesis of exosomes starts when the limiting membrane of endosomes invaginates to form intraluminal
vesicles (ILVs). These endosomes, called multivesicular bodies (MVBs), are then transported to the cell periphery
for the release of the ILVs–the exosomes. While the biogenesis of MVBs is mostly mediated by the ESCRT
complex, the molecular machinery that mediates the transport of MVBs to the cell periphery, and their subsequent
docking and fusion with the plasma membrane for exosome release, remains elusive. In addition, how the
biogenesis and intracellular trafficking of the exosomes are regulated by signaling molecules is largely unknown.
The goal of our research is to identify the basic machinery that mediating the intracellular trafficking of the
exosomes, and to elucidate how oncogenic signaling control these processes for tumor progression. First, we will
study several classes of proteins including the Rab family of small GTPases, the octameric exocyst complex, and
microtubule motor proteins, and understand how they function in concert in the transport, docking and fusion of
MVBs to the plasma membrane. These work will lay the foundation for the basic cell biological understanding of
exosome secretion. Second, we will identify and characterize oncogenic signaling pathways that regulate various
aspects of exosome trafficking, from exosome protein cargo selection, to exosome release at the plasma
membrane. At the functional level, we will study how tumor cell-intrinsic signaling pathways such as the Mitogen-
Activated Protein Kinase (MAPK) axis, through the exosomes, influence tumor microenvironment and the immune
system to promote tumor growth and immune evasion. A multidisciplinary approach that combines biochemistry,
cell biology, tumor biology, and immunobiology will be taken to address these questions. Our study will bridge
basic exosome cell biology to cancer biology. It will not only lay the cell biological foundation for the molecular
and mechanistic understanding of exosomes, but also open new venues for therapeutic targeting of exosomes in
cancer.

## Key facts

- **NIH application ID:** 10205398
- **Project number:** 1R35GM141832-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** WEI GUO
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $507,321
- **Award type:** 1
- **Project period:** 2021-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10205398

## Citation

> US National Institutes of Health, RePORTER application 10205398, Molecular Basis and Regulatory Mechanisms of Exosome Secretion (1R35GM141832-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10205398. Licensed CC0.

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