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This unique metastatic niche consists of a multicellular complex that cancer cells co-opt to engender bone remodeling, immune suppression, and stromal-mediated therapeutic resistance. This review comprehensively discusses clinical challenges of bone metastases, novel preclinical models of the bone and bone marrow microenviroment, and crucial signaling pathways active in bone homeostasis and metastatic niche. These studies establish the context to summarize the current state of investigational agents targeting BM, and approaches to improve BM-targeting therapies. Finally, we discuss opportunities to advance research in bone and bone marrow microenvironments by increasing complexity of humanized preclinical models and fostering interdisciplinary collaborations to translational research in this challenging metastatic niche.<\/jats:p>","DOI":"10.3390\/cancers14030757","type":"journal-article","created":{"date-parts":[[2022,2,1]],"date-time":"2022-02-01T09:59:21Z","timestamp":1643709561000},"page":"757","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Advancing Treatment of Bone Metastases through Novel Translational Approaches Targeting the Bone Microenvironment"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7395-3182","authenticated-orcid":false,"given":"Nan","family":"Sethakorn","sequence":"first","affiliation":[{"name":"University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"Division of Hematology\/Oncology, University of Wisconsin-Madison, 1111 Highland Ave., Madison, WI 53705, USA"},{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0166-9972","authenticated-orcid":false,"given":"Erika","family":"Heninger","sequence":"additional","affiliation":[{"name":"University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"S\u00e1nchez-de-Diego","sequence":"additional","affiliation":[{"name":"University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adeline B.","family":"Ding","sequence":"additional","affiliation":[{"name":"University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi Chandra","family":"Yada","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheena C.","family":"Kerr","sequence":"additional","affiliation":[{"name":"University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Kosoff","sequence":"additional","affiliation":[{"name":"University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"Division of Hematology\/Oncology, University of Wisconsin-Madison, 1111 Highland Ave., Madison, WI 53705, USA"},{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Beebe","sequence":"additional","affiliation":[{"name":"University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua M.","family":"Lang","sequence":"additional","affiliation":[{"name":"University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"Division of Hematology\/Oncology, University of Wisconsin-Madison, 1111 Highland Ave., Madison, WI 53705, USA"},{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"Wisconsin Institutes for Medical Research, 1111 Highland Ave., Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.critrevonc.2019.04.020","article-title":"The evolution and understanding of skeletal complication endpoints in clinical trials of tumors with metastasis to the bone","volume":"139","author":"Hussain","year":"2019","journal-title":"Crit. 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