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However, due to a lack of suitable preclinical modeling tools, its contribution to long-term disease outcome and relevance for therapy remain controversial. Here, we established a genetically engineered mouse model (GEMM) fragment\u2013based tumor model uniquely sustaining a functional network of intratumoral lymphatics that facilitates seeding of fatal peripheral metastases. Multiregimen survival studies and correlative patient data identified primary tumor\u2013derived Angiopoietin-2 (Ang2) as a potent therapeutic target to restrict lymphogenous tumor cell dissemination. Mechanistically, tumor-associated lymphatic endothelial cells (EC), in contrast to blood vascular EC, were found to be critically addicted to the Angiopoietin\u2013Tie pathway. Genetic manipulation experiments in combination with single-cell mapping revealed agonistically acting Ang2\u2013Tie2 signaling as key regulator of lymphatic maintenance. Correspondingly, acute presurgical Ang2 neutralization was sufficient to prolong survival by regressing established intratumoral lymphatics, hence identifying a therapeutic regimen that warrants further clinical evaluation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Exploiting multiple mouse tumor models including a unique GEMM-derived allograft system in combination with preclinical therapy designs closely matching the human situation, this study provides fundamental insight into the biology of tumor-associated lymphatic EC and defines an innovative presurgical therapeutic window of migrastatic Ang2 neutralization to restrict lymphogenous metastasis.<\/jats:p>\n                    <jats:p>This article is highlighted in the In This Issue feature, p. 211<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-20-0122","type":"journal-article","created":{"date-parts":[[2020,10,26]],"date-time":"2020-10-26T08:25:13Z","timestamp":1603700713000},"page":"424-445","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Timed Ang2-Targeted Therapy Identifies the Angiopoietin\u2013Tie Pathway as Key Regulator of Fatal Lymphogenous Metastasis"],"prefix":"10.1158","volume":"11","author":[{"given":"Nicolas","family":"Gengenbacher","sequence":"first","affiliation":[{"name":"1Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany."},{"name":"2Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany."},{"name":"3Faculty of Biosciences, Heidelberg University, Mannheim, 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