Primary tumor-derived systemic nANGPTL4 inhibits metastasis.

Primary tumors and distant site metastases form a bidirectionally communicating system. Yet, the molecular mechanisms of this crosstalk are poorly understood. Here, we identified the proteolytically cleaved fragments of angiopoietin-like 4 (ANGPTL4) as contextually active protumorigenic and antitumorigenic contributors in this communication ecosystem. Preclinical studies in multiple tumor models revealed that the C-terminal fragment (cANGPTL4) promoted tumor growth and metastasis. In contrast, the N-terminal fragment of ANGPTL4 (nANGPTL4) inhibited metastasis and enhanced overall survival in a postsurgical metastasis model by inhibiting WNT signaling and reducing vascularity at the metastatic site. Tracing ANGPTL4 and its fragments in tumor patients detected full-length ANGPTL4 primarily in tumor tissues, whereas nANGPTL4 predominated in systemic circulation and correlated inversely with disease progression. The study highlights the spatial context of the proteolytic cleavage-dependent pro- and antitumorigenic functions of ANGPTL4 and identifies and validates nANGPTL4 as a novel biomarker of tumor progression and antimetastatic therapeutic agent.

Novel pre-clinical mouse models for chronic Graft-versus-Host Disease.

Despite considerable progress in allogeneic hematopoietic cell transplantation (allo-HCT) has been achieved over the past years, chronic Graft-versus-Host Disease (cGvHD) still contributes to high morbidity rates, thus remaining a major hurdle in allo-HCT patients. To understand the complex pathophysiology of cGvHD and to develop refined prophylaxis and treatment strategies, improved pre-clinical models are needed. In this study, we developed two murine cGvHD models, which display high long-term morbidity but low mortality and depict the heterogeneous clinical manifestations of cGvHD seen in patients. We established a haploidentical C57BL/6→B6D2F1 allo-HCT model that uses myeloablative radiation and G-CSF-mobilized splenocytes as stem cell source and a sub-lethally irradiated Xenograft model, which utilizes the transfer of human peripheral blood mononuclear cells (PBMCs) into NOD scid gamma (NSG)-recipients. We characterized both mouse models to exhibit diverse clinical and histopathological signs of human cGvHD as extensive tissue damage, fibrosis/sclerosis, inflammation and B cell infiltration in cGvHD target organs skin, liver, lung and colon and found a decelerated immune cell reconstitution in the late phase after HCT. Our pre-clinical models can help to gain a deeper understanding of the target structures and mechanisms of cGvHD pathology and may enable a more reliable translation of experimental findings into the human setting of allo-HCT.

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 genetically engineered mouse model (GEMM) fragment-based 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-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 presurgical Ang2 neutralization was sufficient to prolong survival by regressing established intratumoral lymphatics, hence identifying a therapeutic regimen that warrants further clinical evaluation. SIGNIFICANCE: 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.This article is highlighted in the In This Issue feature, p. 211.