Exosomes from differentially activated macrophages influence dormancy or resurgence of breast cancer cells within bone marrow stroma

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dc.contributor.authorWalker, Nykia
dc.contributor.authorElias, Michael
dc.contributor.authorGuiro, Khadidiatou
dc.contributor.authorBhatia, Ranvir
dc.contributor.authorGreco, Steven J.
dc.contributor.authorBryan, Margarette
dc.contributor.authorGergues, Marina
dc.contributor.authorSandiford, Oleta A.
dc.contributor.authorPonzio, Nicholas M.
dc.contributor.authorLeibovich, Samuel J.
dc.contributor.authorRameshwar, Pranela
dc.date.accessioned2022-03-24T17:41:57Z
dc.date.available2022-03-24T17:41:57Z
dc.date.issued2019-01-25
dc.description.abstractBreast cancer (BC) cells (BCCs) can retain cellular quiescence for decades, a phenomenon referred to as dormancy. BCCs show preference for the bone marrow (BM) where they can remain dormant for decades. Targeting BCCs within the BM is a challenge since the dormant BCCs reside within BM stroma, also residence for hematopoietic stem cells (HSCs). Dormant BCCs could behave as cancer stem cells (CSCs). The CSCs and HSCs are similar by function and also, by commonly expressed genes. The method by which dormant BCCs transition into clinically metastatic cells remains unclear. This study tested the hypothesis that macrophages (MΦs) within BM stroma, facilitates dormancy or reverse this state into metastatic cells. MΦs exhibiting an M2 phenotype constitute ~10% of cultured BM stroma. The M2 MΦs form gap junctional intercellular communication (GJIC) with CSCs, resulting in cycling quiescence, reduced proliferation and carboplatin resistance. In contrast, MΦs expressing the M1 phenotype reversed BC dormancy. Activation of M2a MΦs via the toll-like receptor 4 (TLR4) switched to M1 phenotype. The switch can occur by direct activation of M2a MΦs, or indirectly through activation of mesenchymal stem cells. M1 MΦ-derived exosomes activated NFкB to reverse quiescent BCCs to cycling cells. Using an in vivo model of BC dormancy, injected Mi MOs sensitized BCCs to carboplatin and increased host survival. In summary, we have shown how BM stromal MΦs, through exosomes, regulate the behavior of BCCs, by either inducing or reversing dormancy.en_US
dc.description.sponsorshipWe thank Mr. Luke Fritzky and Mr. Joel Pierre for assisting with the sectioning of mouse tissues. The work was supported by an award given by the Department of Defense, W81XWH-11-1-0276 to P.R. and by the New Jersey Commission on Cancer Research (NJCCR) pre-doctoral fellowship grant # DFHS15PPC049 to NDW. This work is in partial fulfillment for a Ph.D. thesis for N.D.W.en_US
dc.description.urihttps://www.nature.com/articles/s41419-019-1304-zen_US
dc.format.extent16 pagesen_US
dc.genrejournal articlesen_US
dc.identifierdoi:10.13016/m2clru-ivxs
dc.identifier.citationWalker, N.D., Elias, M., Guiro, K. et al. Exosomes from differentially activated macrophages influence dormancy or resurgence of breast cancer cells within bone marrow stroma. Cell Death Dis 10, 59 (2019). https://doi.org/10.1038/s41419-019-1304-zen_US
dc.identifier.urihttps://doi.org/10.1038/s41419-019-1304-z
dc.identifier.urihttp://hdl.handle.net/11603/24415
dc.language.isoen_USen_US
dc.publisherNatureen_US
dc.relation.isAvailableAtThe University of Maryland, Baltimore County (UMBC)
dc.relation.ispartofUMBC Biological Sciences Department Collection
dc.rightsThis item is likely protected under Title 17 of the U.S. Copyright Law. Unless on a Creative Commons license, for uses protected by Copyright Law, contact the copyright holder or the author.en_US
dc.rightsAttribution 4.0 International (CC BY 4.0)*
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/*
dc.titleExosomes from differentially activated macrophages influence dormancy or resurgence of breast cancer cells within bone marrow stromaen_US
dc.typeTexten_US
dcterms.creatorhttps://orcid.org/0000-0001-7603-9276en_US

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