Basement Membrane-Rich Organoids with Functional Human Blood Vessels Are Permissive Niches for Human Breast Cancer Metastasis.docVIP

Basement Membrane-Rich Organoids with Functional Human Blood Vessels Are Permissive Niches for Human Breast Cancer Metastasis Rodrigo Fernández-Periá?ez 1 , Irene Molina-Privado , Sandra Zazo , Marta Compte , Ana álvarez-Cienfuegos , Ana M. álvarez-Méndez , Laura Sanz , Luis álvarez-Vallina 1* 1 , Federico Rojo 2 , Irene Guijarro-Mu?oz 1 , Vanesa Alonso-Camino 1¤a 2 1 1 , ángel M. Cuesta 1¤b , David Sánchez-Martín 1¤c 3 1 1 Molecular Immunology Unit, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain, 2 Pathology Department, IIS-Fundación Jiménez Díaz, Madrid, Spain, 3 FEBIO Research Group, Universidad Complutense de Madrid, Madrid, Spain Abstract Metastasic breast cancer is the leading cause of death by malignancy in women worldwide. Tumor metastasis is a multistep process encompassing local invasion of cancer cells at primary tumor site, intravasation into the blood vessel, survival in systemic circulation, and extravasation across the endothelium to metastasize at a secondary site. However, only a small percentage of circulating cancer cells initiate metastatic colonies. This fact, together with the inaccessibility and structural complexity of target tissues has hampered the study of the later steps in cancer metastasis. In addition, most data are derived from in vivo models where critical steps such as intravasation/ extravasation of human cancer cells are mediated by murine endothelial cells. Here, we developed a new mouse model to study the molecular and cellular mechanisms underlying late steps of the metastatic cascade. We have shown that a network of functional human blood vessels can be formed by co-implantation of human endothelial cells and mesenchymal cells, embedded within a reconstituted basement membrane-like matrix and inoculated subcutaneously into immunodeficient mice. The ability of circulating cancer cells to colonize