Cancer Biology & Genetics
Memorial Sloan Kettering Cancer Center
Metastasis is the cause of nearly all deaths from cancer, yet the mechanisms that allow cells to move and take hold in new organs is poorly understood. Gaining insight into this process is a key step in turning cancer into a chronic, non-life threatening illness. Studying metastasis in the laboratory has remained a major challenge in the field, in part because existing models do not allow us to capture and perturb each of these steps. My laboratory approaches this problem using the zebrafish, a small freshwater fish that surprisingly develops a number of different cancers, including a well-characterize melanoma model. To study metastasis in real-time, my laboratory developed the transparent casper strain of fish, which allows us to see even the very first cancer cell as it metastasizes and arrives at a new location. When combined with the powerful genetic tools available in the zebrafish, we can interrogate metastasis at an unprecedented scale.
Richard White, M.D., Ph.D. is a physician-scientist at Memorial Sloan Kettering Cancer Center. His laboratory focuses on basic mechanisms of metastasis, the cause of nearly all deaths from solid tumors. He studies this process using the zebrafish, a transparent animal that allows him to visualize and interrogate each step of the metastatic cascade. He grew up in New York, and did his M.D. and Ph.D. degrees at Albany Medical College. He then moved to Yale University for his clinical training in as a Resident in Internal Medicine, and stayed on to serve as Chief Resident. Following this, he went to Boston to complete a fellowship in clinical training in Medical Oncology at the Dana Farber Cancer Institute and Massachusetts General Hospital. It was during his postdoctoral research work at Harvard Medical School that he developed the zebrafish as a model for studying cancer and metastasis. This included both genetic zebrafish models of melanoma, as well as the transparent casper strain of zebrafish. In his laboratory at Sloan Kettering, he is now using these models to interrogate how metastatic cancer cells interact with surrounding non-cancerous cells that make up the tumor microenvironment. His work shows the ways in which seemingly normal cells play major roles in supporting the growth of the cancer cells. Through both genetic and small molecule perturbation of this cellular cross-talk, the zebrafish points the path forward to new possibilities for the treatment of cancer.
Adipocytes in the melanoma microenvironment
It is increasingly clear that cancer cells do not exist in a vacuum – they are surrounded by numerous other cell types in the body that exert dominant effects on their behavior. Collectively, all of the cells surrounding the cancer cells are called the tumor microenvironment. Outside of the immune system, little attention has been paid to the large number of other cell types in the tumor microenvironment, and we feel that many of these other cell types would make excellent therapeutic targets. To address this question, my laboratory has developed an unusual model for studying melanoma – the zebrafish, a transparent animal that offers the unique capacity to visualize cancer from the moment the tumor begins all the way through to metastatic disease.
“Up until recently, little attention has been paid to how seemingly normal cells contribute to cancer metastasis. The Pershing prize will allow us to deeply interrogate the role of adipocytes, which are the fat storing cells scattered throughout every vertebrate, from fish to humans. Our work so far shows that these fat cells directly fuel the metastatic cancer cells, and the Pershing prize will allow us to figure out novel ways to interrupt this connection. Although our work starts in the zebrafish, we believe that our findings will have major therapeutic utility for the treatment of humans with metastatic cancer.”
Using this model, we have uncovered an unexpected interaction between melanoma cells and the fat cells that are normally present beneath the skin. We have shown that these fat cells, also called adipocytes, strongly promote melanoma cell growth and invasion, making the tumor cells more metastatic by directly transferring fat droplets into the melanoma cells. We have identified a specific protein that mediates this fat transfer and have found a chemical that can block it, thereby stopping growth of the tumors. We wish to fully explore how these adipocytes interact with the melanoma cells, using both our zebrafish models but also human tissue specimens. We want to determine whether the chemical we discovered has the potential as a new therapeutic target in melanoma, and in which patients it is likely to be most useful. We believe this proposal takes advantage of a novel system for studying melanoma, and will lead to clinically meaningful insights that can be used to target a new member of the tumor microenvironment.
“Innovation has to start with being wrong. Most research funding is predicated on a high likelihood of success, but if we design experiments that are too safe, too predictable, we are unlikely to find the surprises that often lead to seismic shifts in our thinking. My favorite experiments are ones which are carefully designed, yet have a high chance of leading us somewhere far from where we envisioned we’d wind up.”