RT Journal Article
SR Electronic
T1 Antimetastatic dsRNA mimics identified by live imaging of pathogenic neolymphangiogenesis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2019.12.26.887943
DO 10.1101/2019.12.26.887943
A1 David Olmeda
A1 Daniela Cerezo-Wallis
A1 Tonantzin G. Calvo
A1 Direna Alonso
A1 Estela Cañón
A1 Nuria Ibarz
A1 Javier Muñoz
A1 Sagrario Ortega
A1 María S. Soengas
YR 2019
UL http://biorxiv.org/content/early/2019/12/26/2019.12.26.887943.abstract
AB The crosstalk between cancer cells and the lymphatic vasculature has long been proposed to define competency for metastasis. Nevertheless, the discovery of selective blockers of lymphovascular niches has been compromised by the paucity of experimental systems for whole-body analyses of tumor progression. Here we present immunocompetent and immunodeficient mouse models for live imaging of melanoma-induced neolymphangiogenesis (driven by Vegfr3) as a cost-effective platform for drug screening in vivo. Spatio-temporal analyses in autochthonous melanomas and patient-derived xenografts identified double stranded RNA mimics (dsRNA nanoplexes) as potent repressors of lymphangiogenesis and metastasis. Mechanistically, dsRNA nanoplexes were found to suppress lymphangiogenic drivers in both tumor cells and their associated lymphatic vasculature (via MIDKINE and Vegfr3, respectively). This dual inhibitory action, driven by type I interferon, was not shared by FDA-approved antimelanoma treatments or by lymphangiogenic blockers in clinical testing. These results underscore the power of Vegfr3-lymphoreporters for pharmacological testing in otherwise aggressive cancers.RELEVANCE Although tumor-induced lymphangiogenesis has long been associated with metastasis, selective targeting of this process has been compromised by the paucity of experimental platforms for whole-body imaging of tumor progression and drug response. Here we present animal models engineered for spatio-temporal analyses of neolymphangiogenesis in clinically relevant autochthonous melanomas and patient-derived xenografts, and identify a unique action of double stranded-RNA nanoplexes as potent repressors of lymphatic dissemination and metastatic relapse.GEMMGenetically engineered mouse modelsHLEChuman lymphatic endothelial cellsLNlymph nodePDXpatient-derived xenograftsBO-110bioavailable nanoplexes of (poly)inosinic:polycytidylic acid packed with polyethyleneimine