Mechanisms by which 27-hydroxycholesterol modulates the secretion of extracellular vesicles

Breast cancer remains a global health concern, necessitating the need for continued research in understanding the pathways involved in its progression and in developing new and more targeted therapeutic strategies. Elevated circulating cholesterol has been associated with breast cancer recurrence in pre-clinical as well as clinical models. The cholesterol metabolite, 27-hydroxycholesterol (27HC), has been identified to establish an immunosuppressive tumor microenvironment) in myeloid immune cells. Interestingly, 27HC treatment of different myeloid immune cells results in increased secretion of extracellular vesicles (EVs) with altered cargo. EVs serve as crucial mediators of cell-to-cell communication in normal physiology as well as in diseased states and have been largely studied in regard to their role in cancer progression. However, the mechanisms by which their biogenesis and secretion are regulated by metabolic or endocrine factors remain unknown. Here, we delineate a mechanism by which EV secretion is regulated by 27HC, where treatment of myeloid immune cells (RAW 264.7 and J774A.1) with 27HC impairs lysosomal homeostasis, leading to shunting of multivesicular bodies (MVBs) away from lysosomal degradation, towards secretion as EVs. This altered lysosomal function is likely caused by mitochondrial dysfunction and subsequent increase in reactive oxygen species (ROS). Interestingly, cotreatment with a mitochondria-targeted antioxidant rescued the lysosomal impairment and attenuated the 27HC-mediated increase in EV secretion. Overall, our findings establish how a cholesterol metabolite regulates EV secretion and paves the way for the development of strategies to regulate cancer progression by controlling EV secretion.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Molecular & Integrative Physi

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2024

Author dc:creator

• Das Gupta, Anasuya

Contributors dc:contributor

• Nelson, Erik R
• Bagchi, Milan K
• Boppart, Stephen A
• Boppart, Marni D

• Reactive Oxygen Species
• Mitochondria
• 27-hydroxycholesterol
• Extracellular Vesicles
• Myeloid Immune Cell
• Lysosome

Statement dc:rights

• Copyright 2024 Anasuya Das Gupta

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/127438

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F127438