CellPressCellLeading EdgeReviewMetastasisStefanie Gerstberger,1 Qingwen Jiang,2 and Karuna Ganesh1.2.*1Department of Medicine,Memorial Sloan Kettering Cancer Center,New York,NY,USA2Molecular Pharmacology Program,Sloan Kettering Institute,Memorial Sloan Kettering Cancer Center,New York,NY,USACorrespondence:ganeshk@mskcc.orghttps:/doi.org/10.1016j.cel.2023.03.003SUMMARYMost cancer-associated deaths occur due to metastasis,yet our understanding of metastasis as an evolving,heterogeneous,systemic disease and of how to effectively treat it is still emerging.Metastasis requires theacquisition of a succession of traits to disseminate,variably enter and exit dormancy,and colonize distantorgans.The success of these events is driven by clonal selection,the potential of metastatic cells to dynam-ically transition into distinct states,and their ability to co-opt the immune environment.Here,we review themain principles of metastasis and highlight emerging opportunities to develop more effective therapies formetastatic cancer.INTRODUCTIONdevelopment of new biomarkers and drug targets and rapidlyadvanced our understanding of the underlying biology of howMetastasis,the growth of cancer cells in organs distant from themetastatic cells hijack their host environments to ensure theirone in which they originated,is the ultimate and most lethalsurvival.Here,we review the established paradigms of metas-manifestation of cancer.The vast majority of cancer patientstasis and emerging principles essential for dissemination,die as a consequence of their metastatic disease and not duesurvival,and outgrowth of metastatic cells and also highlightto primary tumors.Metastasis encompasses a series of biolog-recent discoveries and conceptual advances as well as thera-ical events in which cells from a primary tumor progressivelypeutic implications for the treatment of metastatic cancer.acquire the capacity to invade through the mucosa into deepertissues;disseminate through the blood,lymphatics,or throughPHASES OF METASTASISdirect infiltration of neighboring structures;seed distant organs;and eventually resume proliferation at distant sites to colonizeMetastasis can be divided into three phases that can overlap inthese organs.-3 Each of these events is driven by the ability oftime-dissemination,dormancy,and colonization-duringtumor cells to adopt different phenotypic cell states and co-optwhich cancer cells undergo a succession of steps to invadetheir surrounding immune and stromal cells in the tumor environ-tissues,survive in transit,and colonize organs,collectivelyment to support their growth and evade the immune system.4termed the metastatic cascade2(Figure 1).During dissemina-Unlike primary tumors,which often can be cured with local ther-tion,tumor cells harboring oncogenic driver mutations invadeapies such as surgery and radiation,metastatic cancer is a sys-through the basement membrane into deeper tissue layers.temic disease that affects multiple organs,either by directlyacquir
