Spotlight - Nicholas Tolwinski

Signal transduction interested me because of the way in which all cells in a multicelled organism must use it to "talk" to one another. At the time, the field was still in its infancy, which was another draw. There was a great deal of satisfying, results-oriented work being done with some very important pathways.

Knowing I wanted to purse signaling further, I applied to a number of graduate programs, and with Tamiko's guidance, ended up at Princeton's Graduate School of Biomedical Science. Out of the three required rotations, the one that I found most interesting was studying Drosophila, or fruit flies, in a molecular biology laboratory run by Eric Wieschaus, a Nobel Prize-winning developmental biologist.

A Good, Old-Fashioned Intellectual Battle

In Eric's lab, the work I did examined the way that the Wingless/Wnt signaling pathway works in Drosophila. We used newly developed molecular techniques to understand this pathway.  When I started studying the pathway, the field was in the midst of an intellectual battle. The main signaling molecule in this pathway, called beta-catenin, had originally been found to have a structural role. But from the signal transduction point of view, it also had to travel into the cell's nucleus to turn on genes.  Two opposing factions formed.  Some people believed it was a membrane protein, which had nothing to do with the nucleus. Other people believed it was primarily a nuclear protein, and its structural work was a secondary role. My work in Eric's lab sought to solve the controversy.

The nuclear theory faction believed that the Wnt signaling pathway provided important information during development and that mutations in this pathway could lead to various forms of cancer. When functioning properly, the process of Wnt binding to its receptor causes the stabilization and nuclear localization of beta-catenin, which then functions to activate transcription in conjunction with a transcription factor known as TCF. The membrane faction argued that the nuclear localization of beta-catenin was unrelated to its primary function, which is to activate a plasma membrane signaling pathway.

	Dr. Tolwinski with lab members

My first project demonstrated that the nuclear theory was correct. To do this, I developed a complicated experiment that hadn't previously been tried. I showed that that the pathway in fact does depend on the nuclear localization of beta-catenin. We demonstrated that although sending exogenous protein to the membrane did activate signaling, it was because at the same time endogenous protein was going into the nucleus. It was not so much a novel discovery as an elegant way of showing how this process actually works.

An Opportunity Too Good to Ignore

After five years at Princeton, I was ready to go on to do a postdoctoral fellowship. Eric, my advisor, had heard about a new program at Memorial Sloan-Kettering Cancer Center that sounded interesting, called the Frank A. Howard Fellows Program. Named for Frank Howard, who was instrumental in the founding of the Sloan-Kettering Institute and served as its president from 1950 to 1960, the program provides young scientists who have just completed their PhD degrees with an opportunity to establish independent research programs. Senior faculty in the Sloan-Kettering Institute provide mentoring, and the funding allows fellows to establish their own laboratories, hire assistants, and obtain supplies and equipment.

It was an amazing opportunity for a young scientist like me, and I was deeply honored to be chosen as its first recipient. For me, it was a dream job. I came here with the projects I had been working on at Princeton. I was allowed to build my own lab, hire my own staff, and conduct my own research -- all things that are not normally available to postdocs. And I would be living in New York City, which after five years in Princeton, New Jersey, was a big deal!

When I arrived in February 2005, my goal was to use genetic approaches and Drosophila models to study the underlying processes that lead to the formation of cancer, a process known as oncogenesis. My aim was to establish a firm link between oncogenesis and metastasis, or tumor spread. Understanding this linkage could lead to the development of more targeted approaches to treatment, since the prevention of metastasis should help defend against many of the devastating effects of cancer.

Retraining in Cell Biology

In the four years since I have been here, I have accomplished many of my initial goals. Interestingly, one unexpected development is how much my work has veered into the realm of cell biology. I was running out of new directions to go with pure signaling, and I was interested in the subject of cellular polarity, or how cells know direction, that is, how they know up from down. I needed to learn and use cell biology techniques to understand this fascinating process. The retraining process took a long time. Where before things came relatively easily, they were now more difficult. But it was well worth the work, and we have started to produce some very interesting results.

The Developmental Biology Program at Sloan-Kettering Institute, of which I am a member, is a close-knit group of scientists. The atmosphere is very collaborative, and working with so many fellow young scientists is exciting. My collaborative research has included work with Jennifer Zallen, Eric Lai, and the program chair, Kathryn Anderson.

My recent work is focused on demonstrating how normal signaling is involved in the organization of cells within the plane of a tissue. Signaling can affect cell shape, the direction in which the cells create their shape, and the direction of the structures that the cells form. We discovered some very interesting new players in this signaling pathway, and I am excited to publish the results of the work.