Timed Ang2-targeted therapy identifies the Angiopoietin-Tie pathway as key regulator of fatal lymphogenous metastasis.

Recent clinical and preclinical advances have highlighted the existence of a previously hypothesized lymphogenous route of metastasis. 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 GEMM fragment-based tumor model uniquely sustaining a functional network of intratumoral lymphatics that facilitates seeding of fatal peripheral metastases. Multi-regimen survival studies and correlative patient data identified primary tumor-derived 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-Tie pathway. Genetic manipulation experiments in combination with single-cell mapping revealed agonistically-acting Ang2/Tie2-signaling as key regulator of lymphatic maintenance. Correspondingly, acute pre-surgical Ang2-neutralization was sufficient to prolong survival by regressing established intratumoral lymphatics, hence identifying a novel therapeutic regimen that warrants further clinical evaluation.