Seminar

Role of tumor-secreted exosomes in pre-metastatic niche formation, When, Where and How?

Hector Peinado, PhD

Cancer is a systemic disease, while most of the research effort has been focused on analyzing the primary tumor, there is a lack of information on how the tumor microenvironment influences metastasis. The importance of the microenvironment in metastasis is now fully acknowledged. Prominent roles for stromal cells, such as fibroblasts, endothelial cells, lymphatic endothelial cells, bone marrow-derived cells, soluble factors and secreted vesicles have been established. Exosomes are secreted vesicles carrying lipids, proteins, RNA and DNA molecules. By carrying these molecules, and facilitating their cell-to-cell transfer, exosomes can modulate the behavior of resident cells that can impact disease progression. Exosomes can serve as vehicles for horizontal transfer of proteins, RNA and DNA to the surrounding cells, thus promoting additional modifications in the tumor and metastatic microenvironments. Our studies in metastatic melanoma demonstrated that tumor exosomes are a major tumor-derived factor that acts systemically to promote bone marrow-derived cells (BMDCs) recruitment to the tumor and metastatic microenvironments. We showed that exosome secretion by melanoma cells influences BMDC mobilization and recruitment to pre-metastatic and metastatic niches, thus promoting metastasis in a process that we have termed "education". Our novel studies suggest that tumor exosomes can fuse specifically to stromal cells within the metastatic microenvironments. We have analyzed the role of tumor-secreted factors in lymph node and distant metastasis. Our data suggest that tumor-secreted exosomes define the metastatic tropism preparing metastatic niches. Dr. Peinado did his PhD in the laboratory of Dr. Amparo Cano in Madrid (Spain, Biomedical Research Institute "Alberto Sols") where he specialized in analyzing Epithelial to Mesenchymal Transition Mechanisms regulated by Snail transcription factor and Lysyl Oxidase 2 (EMBO J, 2005; Nat. Rev Cancer, 2007). He defined a role for beta-catenin in regulating cancer stem cell behavior in skin cancer (Nature, 2008). He joined Dr. Lyden’s laboratory (Cornell University) as a postdoctoral associate in 2008 to study the crosstalk between tumor cells and bone marrow derived cells during metastatic progression. In 2010, he was appointed to a Faculty Position in the Department of Pediatrics at WCMC and in 2013 promoted to Assistant Professor. Recently, he has defined that tumor-secreted exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype (Nature Medicine, 2012). Since 2015, he leads the Microenvironment and Metastasis laboratory at the CNIO. His current research goals are focused on understanding the crosstalk between the tumor and its microenvironment by secreted factors during lymph node metastasis and determine new targets to block metastasis.