Imaging and targeting premetastatic and niches

Organizers: IRB Barcelona
Date: Friday 31 May, 12.00h
Place: Felix Serratosa Hall, Parc Cientific de Barcelona

Host: Ángel R. Nebreda, PhD - IRB Barcelona

Abstract

MetAlert mice: a platform for whole-body imaging and pharmacological targeting of metastatic niches. David Olmeda¹, Daniela Cerezo-Wallis¹, Tonantzin G. Calvo¹, Paula C. Pennacchi¹, Marta Contreras-Alcalde¹, Xavier Catena¹, Erica Riveiro-Falkenbach², Pablo Ortiz-Romero², José L Rodriguez-Peralto², Sagrario Ortega³ and María S. Soengas¹. ¹Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO). Madrid 28029, Spain. ²Instituto i+12, Hospital Universitario 12 de Octubre, Madrid, Spain, 28041; ³Transgenic Mice Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO). Madrid 28029, Spain.

Metastatic dissemination of cancer cells is a complex process invariably associated with neo-vascularization. Intriguingly, while the presence of malignant cells in lymph nodes is a defining parameter in tumor staging, the specific contribution of the lymphatic vasculature to tumor progression and drug response remains largely unknown. This has been in part due to the scarcity of markers and amenable models for whole-body imaging of neolymphangiogenesis in vivo. Vegfr3 is an attractive “lymphoreporter” as its expression is strongly downregulated in normal adult lymphatic endothelial cells, but gets activated under pathological situations such as inflammation and cancer. Here we exploit immunocompetent and immunodeficient Vegfr3-lymphoreporter mice in the context of malignant melanoma, the most lethal form of skin cancer.  We will show how Vegfr3 imaging revealed pre-metastatic niches activated before the onset tumor cell colonization, and guided in the identification of tumor-secreted pro-metastatic drivers. Moreover, we will present the versatility of our Vegfr3-reporter mice to follow metastatic relapse after surgical excision of primary tumors, as well as to screen for antimetastatic compounds. In particular, we will discuss dsRNA-based nanoparticles with a potent anti-melanoma activity in vivo derived from a three-pronged action: (i) direct tumor-self killing by autophagy, (ii) selective targeting of the lymphangiogenic vasculature, and (iii) activation of innate immunity programs. Importantly, our Vegfr3-reporter mice are not limited to melanoma, as they can be used as a cost-effective “MetAlert” platform for gene discovery and pharmacological testing in a broad spectrum of cancer types.

Plenary Seminar