# Integrin-mediated mechanisms of prostate cancer progression

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $476,796

## Abstract

ABSTRACT
 Therapeutic approaches aimed at curing prostate cancer (PrCa) are only partially successful given the
occurrence of highly metastatic resistant phenotypes that frequently develop in response to chemical castration
of PrCa patients. Recently, we have, for the first time, described αvβ6, a surface receptor of the integrin family
as a novel therapeutic target for PrCa treatment; this molecule is an ideal target since, unlike other integrins, it
is found in different types of cancer but not in normal tissues. We have demonstrated unique properties of this
molecule in PrCa that are not observed for other integrins: we have shown that αvβ6 promotes castrate-
resistant prostate cancer (CRPC) via activation of JNK and androgen receptor (AR). Furthermore, we have
shown that αvβ6 is found in cancer cell exosomes, is transferred from cancer cells to recipient cells by
exosomes and remains active in the recipient cells. We also demonstrate that αvβ6 has profound effects on
the microenvironment. Specifically, αvβ6 prevents induction of the Stat1/Mx1/2 signaling pathway in donor
cancer cells, and their exosomes, and its down-regulation in cancer cell exosomes inhibits monocyte M2
polarization. Finally, we demonstrate that αvβ6 inhibition in vivo causes upregulation of the Stat1/MxA/B
signaling pathway in cancer cells.
 Based on our highly rigorous mechanistic studies, we propose the following innovative hypothesis: αvβ6
expression affects the microenvironment by down-regulating Stat1/Mx1 levels in donor cells, and subsequently
in cancer cell exosomes and recipient cells, thereby promoting monocyte differentiation, tumor growth, and
cancer progression. Consequently, by down-regulating or inhibiting αvβ6 in cancer cells, increased
Stat1/MxA/B levels in cells/ exosomes/ monocytes will be generated producing an anti-tumor effect. To test
this hypothesis, we plan the following three specific aims. We will examine in vitro the role of αvβ6 integrin in
regulating cancer cell - monocyte crosstalk (Aim 1), and analyze in vivo the functional role of the pathway
mediated by exosomal αvβ6 and/or Stat1 in cancer progression (Aim 2) and characterize the αvβ6
integrin/Stat1 pathway in PrCa cells (Aim 3).
 Innovative approaches, highly purified exosomes and in vivo models will be used to test our hypothesis that
transfer of integrins and their downstream effectors from cancer cells to other cells in the tumor
microenvironment promotes CRPC. The study will be supported by a multidisciplinary team of investigators
who have extensive and complementary expertise in all the required technologies. Based on our preliminary
data on the αvβ6/Stat1 pathway and planned experimental design for this project, we expect that our study will
elucidate new mechanisms that promote PrCa and validate new targets for PrCa therapeutic approaches.

## Key facts

- **NIH application ID:** 9970179
- **Project number:** 5R01CA224769-03
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Lucia R. Languino
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $476,796
- **Award type:** 5
- **Project period:** 2018-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970179

## Citation

> US National Institutes of Health, RePORTER application 9970179, Integrin-mediated mechanisms of prostate cancer progression (5R01CA224769-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9970179. Licensed CC0.

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