# Effects of extracellular vesicles on miRNA activity in the skin

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $347,240

## Abstract

PROJECT SUMMARY/ABSTRACT
With more than one million new cases diagnosed yearly, skin cancer accounts for nearly half of all cancers in
the U.S. Squamous cell carcinoma (SCC) is a major form of skin cancer with common genetic signatures, but
without a clear mechanism of oncogenesis. Developing targeted therapies for SCCs has been challenging as
the molecular etiology of the disease paints a heterogeneous picture. An emerging concept is that the synergy
or crosstalk between cancer cells and the tumor microenvironment (TME) is critical for tumor initiation and
progression. Essential for this cell-stroma crosstalk is the role of membrane-derived, nano-sized extracellular
vesicles (EVs) secreted by tumor cells and released into the blood and other bodily fluids carrying their
molecular macromolecular cargo to modulate local and distant TME. In addition to mitogenic signaling proteins
and mRNAs, EVs carry miRNAs, short non-coding RNAs that repress complementary mRNAs critical for cell
cycle regulation and cell proliferation and differentiation. The long-term goal of our research is to understand
at the molecular and cellular level, how normal signaling events during development are subverted for
pathogenic signaling during SCC progression. During malignant transformation, aberrant expression or
localization of the desmosomal cadherin desmoglein 2 (Dsg2) is observed. Dsg2 plays a critical role in normal
cell growth and development, which is emphasized by the fact that genetic ablation results in embryonic cell
growth defects and lethality in mice. In human, mutations in Dsg2 are associated with cardiomyopathy,
respiratory and urinary tract infections, and Alzheimer's disease. Overexpression of Dsg2 also occurs in
various other malignancies including prostate, colon and skin, suggesting a more general role for Dsg2 in
oncogenesis. The mechanism by which Dsg2 promotes cell proliferation, migration, and hyperproliferative
disorders is not fully understood. The goal of this proposal is demonstrate that Dsg2 promotes oncogenesis
by enhancing the release of EVs carrying cancer cell-state specific cargos capable of priming keratinocytes
and fibroblasts. It is our hypothesis that cell surface presentation of Dsg2 modulates export of EV-associated
miRNAs that can serve as biomarkers and key regulators of SCC cancer progression and/or invasion
rendering them novel therapeutic targets. Aim 1 will determine the mechanisms by which Dsg2 modulates the
biosynthesis of EVs. Aim 2 will study the cellular effects of EV-associated miR146a and miR155. Aim 3 will
evaluate the utility of serum EV miRNA levels as prognostic risk factors in SCC. The results obtained here will
elucidate novel functions of Dsg2 and shed new light on how Dsg2 can impact cell growth and migration:
biological steps critical for proper tissue morphogenesis and tumorigenesis. Upon the successful completion of
this work, we will define the mechanisms by which cellular EV export are controlled; how EVs...

## Key facts

- **NIH application ID:** 9933805
- **Project number:** 5R01AR074314-03
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** My Georgia Mahoney
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $347,240
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933805

## Citation

> US National Institutes of Health, RePORTER application 9933805, Effects of extracellular vesicles on miRNA activity in the skin (5R01AR074314-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9933805. Licensed CC0.

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