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Despite this, therapeutic strategies are still predominantly guided by insights from primary tumors, often overlooking the distinct biological features of clinical metastases. In this Review, we provide an overview of current knowledge on clinical metastatic cancer, spanning dissemination, dormancy, colonization, and therapy resistance. We examine the genomic evolution of metastatic clones, including evidence for both early and late dissemination, as well as the impact of treatment-driven selection. Furthermore, we highlight how organ-specific microenvironments shape metastatic outgrowth and therapeutic response and explore how wound-healing and regenerative programs are co-opted during colonization. Finally, we discuss clinical perspectives on treating metastases and outline how advances in single-cell and spatial multi-omics technologies are transforming our ability to interrogate metastatic disease at high resolution, concluding with future perspectives.<\/jats:p>","DOI":"10.1038\/s41388-026-03944-0","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T14:46:13Z","timestamp":1786545973000},"page":"4006-4018","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical metastatic cancer from initiation to colonization: emerging challenges and breakthroughs"],"prefix":"10.1038","volume":"45","author":[{"given":"Guanglin","family":"Niu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5631-7988","authenticated-orcid":false,"given":"Catharina","family":"Hagerling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"3944_CR1","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1038\/s41591-020-01195-4","volume":"27","author":"K Ganesh","year":"2021","unstructured":"Ganesh K, Massague J. 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