Tosato - 2019

Cellular and Molecular Biology Section
NCI
Mentor Name
Giovanna Tosato, M.D.
Hidetaka Ohnuki, Ph.D.
Laboratory And Project Description

The laboratory studies the contribution of blood vessels to the development and progression of cancer. This contribution differs in different contexts. Our laboratory is interested in the contribution of the endothelium to tumor growth in three such contexts. A) Within tumors, the vasculature contributes to accelerate tumor growth by providing nutrients and oxygen to the tumor cells. Drugs that reduce the tumor vascular supply are FDA-approved for the treatment of certain cancers, but their effects are generally modest. We are developing a new approach centered on the function of EphrinB2 signaling that targets the endothelium differently from what has been previously done. Briefly, previous anti-angiogenic drugs prevent new vessel formation, whereas we are targeting the already formed tumor vasculature. B) Within the bone marrow, the vascular endothelium of sinusoidal vessels provides a port of exit for the hematopoietic cells to the peripheral circulation, and from this site reach tumors where they contribute to tumor growth by differentiating into pro-tumorigenic myeloid cells. We have identified a novel mechanism centered on EphB4 signaling whereby the exit of pro-tumorigenic hematopoietic cells can be reduced. We are now further studying and developing this system for potential applications in cancer. C)  Within the intestinal stem cell niche, we are studying the contribution of the endothelium to the development of colon cancer. Our focus is on the interactions between the Notch ligand, Jagged-2, and the intestinal stem cells and other cells within the niche, particularly the endothelium. Ongoing results have identified a number of critical new functions of Jagged-2 in the endothelium that may be critical to colon tumor formation.

In the context of these three main projects, the laboratory has developed a cutting-edge technology to comprehensively analyze the epigenome at a single-cell level. The epigenome represents a form of cell-memory, which records cellular experiences inside the cell. The new technology decodes this cellular memory of individual cells. The laboratory is planning to extend the capabilities of the new technology by integrating additional features of omics technologies. In this project, SIP students will learn various techniques in molecular biology and cutting-edge technologies.

SIP students will be exposed to research on these topics and will be engaged in a specific aspect of one of these projects, commensurate with the candidate expertise, desires, time constrains and probability of success in the experimental part. The candidates will acquire expertise in fields such as vector construction, primers design, protein analysis, flow cytometry, immunohistochemistry and fluorescence microscopy, use of confocal microscopy, animal experimentation.