# Novel Molecular Therapies of Prostate Cancer

> **NIH NIH P01** · WISTAR INSTITUTE · 2021 · $85,800

## Abstract

Project Summary - Project 2 – Funded Parent Award
Project 2 is based on preliminary data demonstrating that prostate cancer6derived exocytosed
microvesicles of endosomal origin, exosomes (EX), containing αv integrins provide a paracrine
mechanism of regulation of prostate cancer cell motility. We have investigated whether the αvβ6
and αvβ3 integrins known to be highly up6regulated in cancer and metastasis, are transferred among
different subsets of prostate cancer cells through EX and have the ability to induce functional
aberrations in the recipient cells. We have recently described that these αv integrins are present in EX
of several prostate cancer cells, are transferred from donor to recipient cells and are localized to the
cell surface indicating they are functional. The quality of our EX preparations, obtained by differential
ultracentrifugation, was tested by electron microscopyJ continuous sucrose gradient, and biochemical
characterization using CD63, CD81 and Flotillin61, as markers known to be enriched in EXJ
furthermore, EX internalization was determined by confocal microscopy. The active state of αv integrins
is confirmed in cell migration assays which show that the αvβ6 integrin, transferred through EX,
promotes cell migration of recipient cells mediated by specific ligands. We show that focal adhesion
kinase and src, known downstream effectors of integrins in cell motility, are localized in EX as active
phosphorylated forms indicating that these microvesicles may transfer entire signaling compartments
to a recipient cell. To evaluate the relevance of our findings, we purified EX from sera of TRAMP
mice, which had developed prostate cancer and show that the αvβ3 integrin is expressed in these EX.
Furthermore, in collaboration with Core B, we show a proteomics analysis of EX (i) and modulation of
EX content in response to downregulation of αvβ6 (ii). These results show a unique EX protein
signature compared with cell lysates and uncover an increase in GRP94 levels in EX upon
downregulation of αvβ6. This study shows that αv integrins are transferred among different subsets of
prostate cancer cells through EX, promote cell migration through interaction with specific ligands, and
are found in EX purified from serum. Based on these data, three specific aims will investigate the
role of the αv integrins delivered by EX in intercellular communications with respect to phenotypic
changes occurring upon uptake of EX by either cancer cells or myeloid6derived suppressor recipient
cells (Aim 1), characterize the role of integrins, their downstream effectors and associated
transmembrane proteins transferred through EX in cancer cell bioenergetics, modulation of the cellular
stress response, and activation of cell motility kinases (Aim 2), and test the composition of EX and role
of EX6mediated prostate cancer progression using SCID mice as well as castrated, prostate6specific
Pten conditional knockout mice (Aim 3).

## Key facts

- **NIH application ID:** 10455831
- **Project number:** 3P01CA140043-11S1
- **Recipient organization:** WISTAR INSTITUTE
- **Principal Investigator:** Dario C Altieri
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $85,800
- **Award type:** 3
- **Project period:** 2010-07-09 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10455831

## Citation

> US National Institutes of Health, RePORTER application 10455831, Novel Molecular Therapies of Prostate Cancer (3P01CA140043-11S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10455831. Licensed CC0.

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