Dr. Pamela Wenzel
Dr. Pamela Wenzel

A molecular stress test has revealed how cancer cells use the lymphatic system to spread throughout the body, report scientists from McGovern Medical School in the journal Nature Communications.

The lymphatic system can be described as a sewer system that rids the body of toxins and waste. Unfortunately, it sometimes takes cancer cells along for the ride.

“We’ve identified a molecular mechanism used by cancer cells to navigate the elaborate network of vessels in the lymphatic system,” said Pamela Wenzel, Ph.D., the study’s senior author and a faculty member in the Department of Pediatric Surgery and the Center for Stem Cell and Regenerative Medicine. “This information promises to pave the way for new treatment options.”

The preclinical study was supported in part by the Cancer Prevention & Research Institute of Texas (RP110776).

“Close collaborations with clinicians and research scientists help to make discoveries quicker and more relevant in diagnosing and curing illness,” said Kevin Lally, M.D., the A.G. McNeese Chair in Pediatric Surgery, Richard J. Andrassy, M.D. Distinguished Chair in Pediatric Surgery and chair of the Department of Pediatric Surgery. Lally is also the surgeon-in-chief of Children’s Memorial Hermann Hospital.

The lymphatic system circulates clear fluid found between tissues and organs called lymph. This fluid picks up debris along the way, which is later cleared from the system.

“We studied the impact that mechanical stress can have on cancer cells as they travel through the lymphatic system,” Wenzel said. “We were able to link the YAP1 proto-oncogene to the migrating cancer cells. A proto-oncogene is a gene that has the potential to cause or advance the progression of cancer.”

YAP1 is a non-cancerous gene under normal circumstances, but it can promote the spread of cancer cells when exposed to a certain level of mechanical force, Wenzel said. “The hope is that one day we will develop a way to inhibit the activity of YAP1 and in turn stop the spread of cancer,” Wenzel said.

Lymphatic capillaries are specialized to take up foreign materials and immune cells for transiting to lymph nodes to trigger immune responses.  When cancer cells metastasize, they are taken up by these lymphatic capillaries and once inside the lymphatics, they can arrest the immune response, said Eva Sevick-Muraca, Ph.D., study co-author and chair of the Center for Molecular Imaging in the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases.

The study focused on cancers affecting the breast and prostate. To evaluate malignancy of these cancers, doctors typically take biopsies of lymph nodes. Together, these cancers claim about 67,000 lives in the United States annually.

“We looked at how fluid mechanical forces impact cellular behavior and migration as cancer cells travel to the lymph nodes,” Wenzel said.

The study involved human cancer in a mouse model. With the aid of special whole body fluorescent imaging, the researchers were able to observe the cancer cells as they moved through the lymphatic system.

In addition, they measured activity of the YAP1 proto-oncogene in cancer cells. “Fluid frictional force causes YAP1 to activate the DNA in the cell’s nucleus, which causes the cell to migrate,” Wenzel said. “We believe that this increased migration contributes to metastasis implicating YAP1 as a new potential target for cancer therapies.”

Wenzel’s co-authors at UTHealth include Hyun Jung Lee, Ph.D.; Miguel F. Diaz; Katherine M. Price; Joyce A. Ozuna; Songlin Zhang, M.D., Ph.D.; and John P. Hagan, Ph.D.

The study, “Fluid shear stress activates YAP1 to promote cancer cell motility,” received support from the State of Texas Emerging Technology Fund, the Cancer Prevention & Research Institute of Texas, American Society of Hematology Scholar Award, Mission Connect: a program of the TIRR Foundation, and National Institutes of Health (grant number K01DK092365).

Wenzel, Sevick-Muraca and Hagan are on the faculty of The University of Texas Graduate School of Biomedical Sciences at Houston, a partnership of UTHealth and The University of Texas MD Anderson Cancer Center. Sevick-Muraca is the Nancy and Rich Kinder Distinguished Chair in Cardiovascular Disease Research at UTHealth.