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Modulation of the pre-metastatic bone niche: molecular changes mediated by bone-homing prostate cancer extracellular vesicles

Brown, Thomas J.; Rutland, Cantrin S.; Rutland, Catrin S.; Choi, Katie K.; Tse, Feng; Pfeffers, Mandy J.; Peffers, Mandy J.; Mongan, Nigel P.; Arkill, Kenton P.; Ritchie, Alison; Clarke, Philip A.; Ratan, Hari; Allegrucci, Cinzia; Grabowska, Anna M.; James, Victoria

Modulation of the pre-metastatic bone niche: molecular changes mediated by bone-homing prostate cancer extracellular vesicles Thumbnail


Authors

Thomas J. Brown

CATRIN RUTLAND CATRIN.RUTLAND@NOTTINGHAM.AC.UK
Professor of Molecular Medicine

Catrin S. Rutland

Katie K. Choi

Feng Tse

Mandy J. Pfeffers

Mandy J. Peffers

NIGEL MONGAN nigel.mongan@nottingham.ac.uk
Associate Pro-Vice Chancellorglobal Engagement

Alison Ritchie

Philip A. Clarke

Hari Ratan

Anna M. Grabowska

VICTORIA JAMES VICTORIA.JAMES@NOTTINGHAM.AC.UK
Professor of Molecular Biology



Abstract

Prostate cancer (PCa) is a leading male malignancy worldwide, often progressing to bone metastasis, with limited curative options. Extracellular vesicles (EVs) have emerged as key players in cancer communication and metastasis, promoting the formation of supportive microenvironments in distant sites. Our previous studies have highlighted the role of PCa EVs in modulating osteoblasts and facilitating tumor progression. However, the early pre-metastatic changes induced by PCa EVs within the bone microenvironment remain poorly understood. To investigate the early effects of repeated exposure to PCa EVs in vivo, mimicking EVs being shed from the primary tumor, PCa EVs isolated from cell line PC3MLuc2a were fluorescently labelled and repeatedly administered via tail vein injection to adult CD1 NuNu male mice for a period of 4 weeks. In vivo imagining, histological analysis and gene expression profiling were performed to assess the impact of PCa EVs on the bone microenvironment. We demonstrate for the first time that PCa EVs home to both bone and lymph nodes following repeated exposures. Furthermore, the accumulation of EVs within the bone leads to distinct molecular changes indicative of disrupted bone homeostasis (e.g., changes to signaling pathways such as Paxillin p = 0.0163, Estrogen Receptor p = 0.0271, RHOA p = 0.0287, Ribonucleotide reductase p = 0.0307 and ERK/MAPK p = 0.0299). Changes in key regulators of these pathways were confirmed in vitro on human osteoblasts. In addition, our data compares the known gene signature of osteocytes and demonstrates a high proportion of overlap (52.2%), suggesting a potential role for this cell type in response to PCa EV exposure. No changes in bone histology or immunohistochemistry were detected, indicating that PCa EV mediated changes were induced at the molecular level. This study provides novel insights into the alterations induced by PCa EVs on the bone microenvironment. The observed molecular changes indicate changes in key pathways and suggest a role for osteocytes in these EV mediated early changes to bone. Further research to understand these early events may aid in the development of targeted interventions to disrupt the metastatic cascade in PCa.

Citation

Brown, T. J., Rutland, C. S., Rutland, C. S., Choi, K. K., Tse, F., Pfeffers, M. J., …James, V. (2024). Modulation of the pre-metastatic bone niche: molecular changes mediated by bone-homing prostate cancer extracellular vesicles. Frontiers in Cell and Developmental Biology, 12, Article 1354606. https://doi.org/10.3389/fcell.2024.1354606

Journal Article Type Article
Acceptance Date Jan 29, 2024
Online Publication Date Feb 22, 2024
Publication Date Feb 22, 2024
Deposit Date Feb 12, 2024
Publicly Available Date Feb 21, 2024
Journal Frontiers in Cell and Developmental Biology
Electronic ISSN 2296-634X
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
Volume 12
Article Number 1354606
DOI https://doi.org/10.3389/fcell.2024.1354606
Keywords Extracellular vesicles, prostate cancer, bone metastasis, pre-metastatic niche, osteocytes
Public URL https://nottingham-repository.worktribe.com/output/31439321
Publisher URL https://www.frontiersin.org/articles/10.3389/fcell.2024.1354606/full
PMID 38455075

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Modulation of the pre-metastatic bone niche: molecular changes mediated by bone-homing prostate cancer extracellular vesicles (3 Mb)
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Licence
https://creativecommons.org/licenses/by/4.0/

Publisher Licence URL
https://creativecommons.org/licenses/by/4.0/

Copyright Statement
© 2024 Brown, Rutland, Choi, Tse, Peffers, Mongan, Arkill, Ritchie, Clarke, Ratan, Allegrucci, Grabowska and James. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.





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