Biochemistry and Cell Biology
Stony Brook University School of Medicine
Metastasis is the primary cause of death in cancer patients. The progression and movement of cancer cells through the circulatory system is one of the least understood aspects of metastasis because it is extremely difficult to visualize using traditional models. However, using light-sheet imaging in a zebrafish xenograft cancer model, we are able to see for the first time circulating tumor cell behaviors at high resolution. These observations have led to a specific model of how cancer cells are exiting the blood vessels, through interactions with white blood cells and co-option of their behaviors. We envision the application of our model of cancer cell behavior in therapeutics to stop the spread of cancer and improve patient outcomes.
Dr. Ben Martin is an Associate Professor in the Department of Biochemistry and Cell Biology at Stony Brook University, and a member of the Stony Brook Cancer Center. His interest in cancer research originates from his love of developmental biology. Cancer initiation and disease progression is highly correlated with the reactivation of genetic and cellular programs that are critical for embryonic development. The foundation of knowledge and tools used for his developmental biology research has set the stage for his work using light-sheet imaging to visualize cancer metastasis in the zebrafish xenograft model. Dr. Martin grew up in the Philadelphia area and received his bachelor’s degree in biochemistry from Bowdoin College in 1999. He pursued his blossoming interest in developmental biology during his Ph.D. studies at the University of California, Berkeley, working in the laboratories of Dr. Richard Harland and Dr. Sharon Amacher. There he studied the genetic and cellular mechanisms of skeletal muscle formation during development using the Xenopus laevis and zebrafish vertebrate model systems. After receiving his Ph.D. in 2005, he moved to the University of Washington, where he was an American Cancer Society postdoctoral fellow in the laboratory of David Kimelman, studying stem cell biology in the developing zebrafish embryo. Dr. Martin started his own lab at Stony Brook University in 2012 and is a recipient of the National Science Foundation Career Award and the Damon Runyon-Rachleff Innovation Award.
Mechanisms of cancer cell extravasation
The overwhelming cause of death in cancer patients with solid tumors is the result of metastasis from the primary tumor to new sites in the body. There is a critical need to better understand the process of metastasis to improve patient outcomes. Many aspects of metastatic disease progression remain a mystery due to the inability to visualize the process in an in vivo setting at high resolution. In this proposal, we will pair state of the art light-sheet imagining with an up-and-coming zebrafish xenograft model to achieve an unprecedented level of understanding about how circulating tumor cells are able to exit blood vessels and invade new sites in the body.
“Our light sheet imaging of circulating human tumor cells in the zebrafish has provided novel insights into the mechanisms of cancer metastasis. We are now poised to make major progress in understanding how circulating tumor cells behave during their dispersal to new sites in the body. The Pershing Square Sohn Prize provides us with the opportunity to go after these new insights so that we can reveal mechanisms of metastasis that can one day be targeted in a rational way to stop the spread of cancer in patients.”
Zebrafish larvae are transparent, allowing for the direct visualization of transplanted human cancer cells traversing the circulatory system and exiting blood vessels. Our preliminary data using this system supports a long-standing model in the cancer field that circulating tumor cells co-opt normal white blood cell behaviors when they exit into surrounding tissues. This preliminary data raises critical questions that we will address in this proposal; how do circulating tumor cells initially adhere to the endothelial lining of the blood vessel, and what are the consequences of disrupting this adhesion? And do circulating tumor cells have an innate ability to cross the blood vessel wall, or do they require assistance from white blood cells? This work will shed light on never-before-seen details of metastasizing cancer cells and provide essential insight into how to target molecular and cellular processes involved in metastasis.
“Innovation arises from novel technologies or intellectual insights that allow you to examine a scientific question in a new light, and ultimately drives progress towards accomplishing a specific goal. Our innovation is seated in the ability to observe cancer cell behavior in a native environment at extremely high resolution, which will teach us about aspects of cancer behavior that we never even thought to ask, simply because we could not see them.”