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Their cellular and molecular drivers remain poorly understood, partly due to limited preclinical models that fail to capture patient tumor heterogeneity. Cancer stem\u2010like cells (CSCs) are implicated in metastatic dissemination; however, their specific role in brain metastasis remains unclear. In this study, CSCs are isolated from human BCBM specimens and characterized for stem\u2010like properties, including CD44 and ALDH1 expression, sphere formation, tumorigenicity, and in vitro and in vivo self\u2010renewal. Intra\u2010nipple and intra\u2010cardiac xenograft models demonstrate CSC ability to generate brain and bone metastases that recapitulate patient\u2010specific dissemination patterns. Transcriptomic and functional analyses reveal cellular heterogeneity and identify a metastasis\u2010initiating cell (MIC) subpopulation enriched in stemness and adhesion\u2010related pathways. These MICs exhibit enhanced adhesion to brain endothelium and undergo brain\u2010specific transcriptomic reprogramming that enables vascular co\u2010option, resistance to stromal stress, and survival\u2010promoting interactions with brain\u2010resident cells. High\u2010throughput drug screening indicates broad therapeutic resistance within the CSC compartment. Through the comprehensive characterization of BCBM\u2010derived CSCs, this study establishes a clinically relevant model that identifies CSCs and the MIC subpopulation as key drivers of brain metastatic progression and as promising targets for the development of effective therapeutic strategies.<\/jats:p>","DOI":"10.1002\/adhm.202505789","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T11:45:02Z","timestamp":1774611902000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Deciphering the Role of Cancer Stem Cells in Breast Cancer Brain Colonization Using a Novel Patient\u2010Derived Model"],"prefix":"10.1002","volume":"15","author":[{"given":"Stefania","family":"Faletti","sequence":"first","affiliation":[{"name":"Department of Experimental Oncology IRCCS European Institute of Oncology (IEO)  Milan 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