Cycling for Cancer and Zebrafish

James Dutko, PhD, a postdoctoral researcher at the Perelman School of Medicine 's Department of Cell and Developmental Biology, spent a hot Sunday morning earlier this month cycling in the 41^st annual Philadelphia Bike-a-Thon, an annual fundraising event for the American Cancer Society (ACS).  

“This year the event brought in 1.1 million dollars to the ACS and its mission to overcome the disease of cancer,” says Dutko. “The Philadelphia bike-a-thon is well organized and accessible to anyone who enjoys riding a bike.” Dutko, pictured here with his wife, rode 65 miles, one of seven distance options, and was supported by family and friends with their donations to the ACS.

Dutko rides his bike everyday to the lab, a time when he does some creative thinking about science. Back when he was working toward his doctorate at the SUNY, Albany, he raced with the Capital Bicycle Racing Club in upstate New York.  Dutko’s ACS fellowship brought him in contact with the organizers of the Philadelphia bike‑a-thon, which he found to be an ideal way to contribute to the fundraising efforts of the ACS.

His ACS research fellowship in the lab of Mary Mullins, PhD, professor of Cell and Developmental Biology, allows him to study characteristics of the bone morphogenetic protein (BMP) signaling pathway and how it contributes to the disease of cancer. He investigates how the pathway normally works in the zebrafish, a seemingly odd model for human cancer studies.

Over the last 20 years, zebrafish have become great models for studying development and disease. Like humans, zebrafish are vertebrates, and most of the genes required for normal embryonic development in zebrafish are also present in humans. When incorrectly regulated, these same genes often cause tumor formation and metastatic cancers.

The earliest function of BMPs is to tell cells in the embryo whether to become front or back tissue. BMP signaling is known to intersect at multiple regulatory steps during tumor formation and in the disease progression of cancer, for example, some tumors hijack BMP to grow their own blood vessels. Aberrant BMP activity has been found in a host of cancers including colon, liver, pancreatic, myeloma, breast, and skin.

Specifically, Dutko studies BMP mutations in zebrafish that cause defects in how cells send signals to each other. A consequence of signaling is that some cells are instructed to differentiate, or display specialized characteristics, such as where to reside in the adult animal or to become a certain cell type, tissue or organ. They do so by expressing different sets of genes in response to the BMP signal. 

Cycling permeates Dutko’s view of the world and he likens his work in cell-cell communication to racing:

Generating a complex structure like an organ requires that cells within the organ communicate with each other. Tumor cells use the same molecules as normal cells to communicate which, in some cases, can be used to our advantage to fight the cancerous cells. In a bike race, riders move about in the peloton in the early stages with no specific job to perform but as the finish line approaches some riders are instructed to the front of the peloton to perform the specific job of leading out their sprinter for the win. Some of the cells in a tumor are like the riders waiting for a job to perform, they are called cancer stem cells, and it is thought that those cells might be able to be targeted by messages which could force them to suspend their self-renewing characteristics. 

When the BMP-controlled cell communication goes wrong, the development of the zebrafish embryo can be completely thrown off track, so much so that it causes it to literally burst at its seams. The time-lapse video of zebrafish embryos, below, shows about twelve hours of development, starting at about six hours after fertilization. On the left is a wild-type, unmutated embryo. On the right is a mutant embryo which has a loss-of-function mutation in the bmp7 gene. BMP signaling is normal in the wild-type embryo and it develops normal body axes. In the bmp7 mutant embryo, BMP signaling is completely inactive and a major body axis fails to develop. This ultimately causes the embryo to die before one day of development.

Dutko considers the progressive development of the embryo and the progression of cancer as two sides of the same coin as cells undergo the opposite process to become cancerous. So, in some cases, BMP signaling can be a barrier to malignant transformation. Equally, the growth and survival of a tumor requires communication between cells at which the BMP pathway is known to intersect - BMP signaling can also enable malignant transformation. 

Recently Mullins described some intriguing aspects of the BMP signaling mechanism that are essential to the development of the embryo. They showed that a BMP signaling gradient guides cells in the embryo to form correctly along the head-to-tail axis. During embryo development, the head-to-tail and front-to-back line-up of cells is specified by the activity of key signaling proteins. An active BMP pathway specifies a cell to become the front and BMP inactivity defines cells on the back, and this active/inactive gradient is synchronized with the signaling proteins that pattern cells from head‑to‑tail.

“By studying BMP signaling during normal development we hope to gain insight into the corrupted signaling pathways that are found in many types of cancer," a notion, says Dutko, whose contemplation makes his ride to and from work go very fast.