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dc.contributor.authorBock, Nathalie
dc.contributor.authorShokoohmand, Ali
dc.contributor.authorKryza, Thomas
dc.contributor.authorRohl, Joan
dc.contributor.authorMeijer, Jonelle
dc.contributor.authorTran, Phong A
dc.contributor.authorNelson, Colleen C
dc.contributor.authorClements, Judith A
dc.contributor.authorHutmacher, Dietmar W
dc.date.accessioned2019-09-27T04:53:02Z
dc.date.available2019-09-27T04:53:02Z
dc.date.issued2019
dc.identifier.issn2095-4700
dc.identifier.doi10.1038/s41413-019-0049-8
dc.identifier.urihttp://hdl.handle.net/10072/387856
dc.description.abstractWhile stromal interactions are essential in cancer adaptation to hormonal therapies, the effects of bone stroma and androgen deprivation on cancer progression in bone are poorly understood. Here, we tissue-engineered and validated an in vitro microtissue model of osteoblastic bone metastases, and used it to study the effects of androgen deprivation in this microenvironment. The model was established by culturing primary human osteoprogenitor cells on melt electrowritten polymer scaffolds, leading to a mineralized osteoblast-derived microtissue containing, in a 3D setting, viable osteoblastic cells, osteocytic cells, and appropriate expression of osteoblast/osteocyte-derived mRNA and proteins, and mineral content. Direct co-culture of androgen receptor-dependent/independent cell lines (LNCaP, C4-2B, and PC3) led cancer cells to display functional and molecular features as observed in vivo. Co-cultured cancer cells showed increased affinity to the microtissues, as a function of their bone metastatic potential. Co-cultures led to alkaline phosphatase and collagen-I upregulation and sclerostin downregulation, consistent with the clinical marker profile of osteoblastic bone metastases. LNCaP showed a significant adaptive response under androgen deprivation in the microtissues, with the notable appearance of neuroendocrine transdifferentiation features and increased expression of related markers (dopa decarboxylase, enolase 2). Androgen deprivation affected the biology of the metastatic microenvironment with stronger upregulation of androgen receptor, alkaline phosphatase, and dopa decarboxylase, as seen in the transition towards resistance. The unique microtissues engineered here represent a substantial asset to determine the involvement of the human bone microenvironment in prostate cancer progression and response to a therapeutic context in this microenvironment.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherNature Publishing Group
dc.relation.ispartofissue1
dc.relation.ispartofjournalBone Research
dc.relation.ispartofvolume7
dc.subject.fieldofresearchClinical sciences
dc.subject.fieldofresearchcode3202
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsCell & Tissue Engineering
dc.subject.keywordsCell Biology
dc.subject.keywordsOSTEOCLASTIC ACTIVITY
dc.titleEngineering osteoblastic metastases to delineate the adaptive response of androgen-deprived prostate cancer in the bone metastatic microenvironment
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationBock, N; Shokoohmand, A; Kryza, T; Rohl, J; Meijer, J; Tran, PA; Nelson, CC; Clements, JA; Hutmacher, DW, Engineering osteoblastic metastases to delineate the adaptive response of androgen-deprived prostate cancer in the bone metastatic microenvironment, Bone Research, 2019, 7 (1)
dcterms.dateAccepted2019-03-04
dcterms.licensehttp://creativecommons.org/licenses/by/4.0/
dc.date.updated2019-09-27T04:49:40Z
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
gro.hasfulltextFull Text
gro.griffith.authorHutmacher, Dietmar W.
gro.griffith.authorShokoohmand, Ali


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