# Exosome-mediated mechanisms of metastatic disease in non-small cell lung cancer

> **NIH VA I01** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2021 · —

## Abstract

Lung cancer is the leading cause of cancer death among US Veterans, and metastatic disease is overwhelmingly
the predominant cause of death. Based on our preliminary findings, we hypothesize that exosomes derived from
highly motile premalignant cells can transfer metastatic phenotypes to neighboring normal cells via paracrine
signaling. In the current Veteran Affairs (VA) Merit Review funding period, we identified and selected a
subpopulation of highly migratory premalignant airway epithelial cells that were observed to migrate through
microscale constrictions at up to 100-fold the rate of the control unselected cells. These highly migratory cells
demonstrate enhanced metastatic behavior in vivo. We isolated and characterized exosomes from these highly
migratory premalignant human airway epithelial cells, as well as, malignant pleural effusion (MPE)-derived
metastatic cancer cells. In both settings of premalignancy and metastatic disease, exosomes containing unique
omic signatures transferred the metastatic phenotype to non-motile cells. From these signatures, we have
identified potential candidates mediating the transfer of metastatic behavior and immunosuppression. To
facilitate the study of metastatic disease, we will utilize our MPE-biobank for exosome isolation and
characterization from individual patient's MPE-derived metastatic lung cancer cells. While exosomes are known
to serve as functional mediators in cell interaction leading to cancer metastasis, this will be the first
comprehensive study to fully characterize the mechanisms underlying these events in the context of pulmonary
premalignant migration, as well as, in the context of metastatic cells from MPEs. In order to characterize and
understand the mechanisms of this process in regulating the promotion of migratory capacity and
immunosuppression in premalignant and metastatic lung cancer cells we will: 1) Determine the capacity of
exosomes to drive disease progression across the spectrum of disease in NSCLC by characterizing the
exosomal cargo derived from premalignant and metastatic cancer cells, 2) Determine the mechanisms of
exosome-dependent promotion of epithelial mesenchymal transition (EMT) and migratory capacity of epithelial
and lung cancer cells and, 3) determine the mechanisms of exosome-dependent immune suppression. While
exosomes have been reported to serve as functional mediators in cellular interaction leading to cancer
metastasis, this will be the first comprehensive study to fully characterize the mechanisms underlying the full
spectrum of disease, both in the context of pulmonary premalignant migration as well as metastatic lung cancer.
This study of exosome mediated metastatic-modulation in the context of premalignancy and metastasis is unique
and will help define the biology of occult metastasis, provide insights into the phenomenon of parallel
progression, increase the possibility of biomarker discovery and provide targets for lung cancer interception.

## Key facts

- **NIH application ID:** 9784401
- **Project number:** 1I01BX004717-01
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** Steven M. Dubinett
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2020-10-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9784401

## Citation

> US National Institutes of Health, RePORTER application 9784401, Exosome-mediated mechanisms of metastatic disease in non-small cell lung cancer (1I01BX004717-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9784401. Licensed CC0.

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