Prostate cancer extracellular vesicles mediate intercellular communication with bone marrow cells and promote metastasis in a cholesterol-dependent manner

Stephen E. Henrich, Kaylin M. McMahon, Michael P. Plebanek, Andrea E. Calvert, Timothy J. Feliciano, Samuel Parrish, Fabio Tavora, Anthony Mega, Andre De Souza, Benedito A. Carneiro*, C. Shad Thaxton*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Primary tumours can establish long-range communication with distant organs to transform them into fertile soil for circulating tumour cells to implant and proliferate, a process called pre-metastatic niche (PMN) formation. Tumour-derived extracellular vesicles (EV) are potent mediators of PMN formation due to their diverse complement of pro-malignant molecular cargo and their propensity to target specific cell types (Costa-Silva et al., 2015; Hoshino et al., 2015; Peinado et al., 2012; Peinado et al., 2017). While significant progress has been made to understand the mechanisms by which pro-metastatic EVs create tumour-favouring microenvironments at pre-metastatic organ sites, comparatively little attention has been paid to the factors intrinsic to recipient cells that may modify the extent to which pro-metastatic EV signalling is received and transduced. Here, we investigated the role of recipient cell cholesterol homeostasis in prostate cancer (PCa) EV-mediated signalling and metastasis. Using a bone metastatic model of enzalutamide-resistant PCa, we first characterized an axis of EV-mediated communication between PCa cells and bone marrow that is marked by in vitro and in vivo PCa EV uptake by bone marrow myeloid cells, activation of NF-κB signalling, enhanced osteoclast differentiation, and reduced myeloid thrombospondin-1 expression. We then employed a targeted, biomimetic approach to reduce myeloid cell cholesterol in vitro and in vivo prior to conditioning with PCa EVs. Reducing myeloid cell cholesterol prevented the uptake of PCa EVs by recipient myeloid cells, abolished NF-κB activity and osteoclast differentiation, stabilized thrombospondin-1 expression, and reduced metastatic burden by 77%. These results demonstrate that cholesterol homeostasis in bone marrow myeloid cells regulates pro-metastatic EV signalling and metastasis by acting as a gatekeeper for EV signal transduction.

Original languageEnglish (US)
Article numbere12042
JournalJournal of Extracellular Vesicles
Volume10
Issue number2
DOIs
StatePublished - Dec 2020

Keywords

  • bone
  • cholesterol
  • exosomes
  • extracellular vesicles
  • metastasis
  • myeloid
  • pre-metastatic niche
  • prostate cancer

ASJC Scopus subject areas

  • Cell Biology
  • Histology

Fingerprint

Dive into the research topics of 'Prostate cancer extracellular vesicles mediate intercellular communication with bone marrow cells and promote metastasis in a cholesterol-dependent manner'. Together they form a unique fingerprint.

Cite this