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Children's Research Institute Year In Review

July 03, 2017 - Promise Magazine

By Katie Regan

The foresight and generosity of leading foundations and individuals has set the stage for remarkable discoveries by researchers in the Children’s Medical Center Research Institute at UT Southwestern. These milestones from 2016 are just a sampling of innovative, groundbreaking projects and studies taking place at CRI.

Research

REVERSING OSTEOPEROSIS WITH A NEW BONE-FORMING GROWTH FACTOR

Dr. Ralph DeBerardinis

Osteoporosis, a progressive bone disease characterized by decreased bone mass and an increase in fractures, affects over 200 million people worldwide. Most existing therapies reduce the rate of bone loss, but they do not promote new bone growth.

Research conducted in Dr. Sean Morrison’s lab last year uncovered a new bone-forming growth factor, Osteolectin (Clec11a), which promotes bone growth and reverses bone loss after the onset of osteoporosis in mice. Deletion of Osteolectin in mice accelerates bone loss during aging, reducing bone strength and delaying fracture healing.

“These results demonstrate the important role Osteolectin plays in new bone formation and maintaining adult bone mass. This study opens up the possibility of using this growth factor to treat diseases like osteoporosis,” said Dr. Sean Morrison, director of the CRI, principal investigator of the Hamon Laboratory for Stem Cell and Cancer Biology, and holder of the Kathryne and Gene Bishop Distinguished Chair in Pediatric Research and the Mary McDermott Cook Chair in Pediatric Genetics. He is also an investigator in the Howard Hughes Medical Institute and a professor in the CRI and of pediatrics.

These early results are encouraging, suggesting Osteolectin might one day be a useful therapeutic option for osteoporosis and in regenerative medicine. These results were published in the scientific journal eLife in December.

MAPPING METABOLIC PATHWAYS IN CANCER TO IMPROVE DIAGNOSIS AND TREATMENT

Proper control of metabolism is required for essentially every basic biological process, including cell growth and division. Altered cellular metabolism is a hallmark of cancer, as cancer cells must reprogram their metabolism to support excessive cell growth. Finding and understanding how these growth-promoting metabolic changes occur in cancer is a key step toward developing new anti-cancer therapies.

In 2016, researchers from Dr. Ralph DeBerardinis’ lab made two important discoveries. In February, the DeBerardinis team pioneered techniques to measure cancer metabolism directly in human tumors, providing the most comprehensive and accurate views of tumor metabolism to date. Traditionally, lung tumors are diagnosed using a clinical form of glucose imaging called FDG-PET scanning because increased glucose (sugar) uptake is a well-known feature of human lung cancer cells. It was unknown, however, how these tumors use glucose to fuel their metabolism.

The DeBerardinis laboratory scientists mapped the fate of glucose in human lung tumors and identified several metabolic differences between tumors and healthy lung tissue. They also showed that individual tumors, and even regions within the same tumor, used strikingly different metabolic activities to generate energy.

Dr. Chao Xing, Mohammed Kanchwala, Dr. Hao Zhu and Dr. Xuxu Sun (from left)

The team also demonstrated that a magnetic resonance imaging technique could predict metabolic behavior in tumors before surgery, providing a completely new approach to study metabolism in human cancer. This work is expected to lead to better ways to exploit metabolic alterations to improve cancer diagnosis and therapy, especially when applied to childhood cancers.

Dr. DeBerardinis is director of the CRI Genetic and Metabolic Disease Program, a professor in the CRI, in the Eugene McDermott Center for Human Growth and Development, and of pediatrics. He holds the Joel B. Steinberg, M.D., Chair in Pediatrics and is a Sowell Family Scholar in Medical Research.

In April, scientists from the DeBerardinis lab identified a novel metabolic pathway that helps cancer cells thrive in conditions that are lethal to normal cells. Researchers found cancer cells use an alternate version of two well-known metabolic pathways to adapt to the stress associated with cancer progression and defend against the reactive oxygen species that kill cells via oxidative stress. Most normal cells are killed after detaching from a support structure called extracellular matrix, because attachment to the matrix keeps oxidative stress at manageable levels. The DeBerardinis lab team found that cancer cells have the ability to activate a novel pathway that counteracts oxidative stress after matrix detachment. This allows them to survive and grow under such conditions.

This discovery has the potential to lead to new cancer therapies, particularly therapies aimed at preventing cancer metastasis, which requires that cells survive a period of matrix detachment. Ongoing work will determine if this metabolic pathway, so far characterized in cultured cancer cells, is required for metastasis in animal models of cancer.

IMPROVING OUR UNDERSTANDING OF THE LINK BETWEEN CANCER AND TISSUE INJURY

Dr. Hao Zhu

Chronically damaged tissues are more likely to develop cancer, but it is unclear if tissue regeneration itself promotes or inhibits the development of cancer. Understanding the relationship between injury, regeneration, and cancer is key to discovering new treatments that could promote tissue regeneration and prevent or delay cancer.

Research from Dr. Hao Zhu’s lab in 2016 provided new insights into the link between tissue regeneration and cancer in the liver. In humans, a gene called ARID1A is inactivated in several cancers, including liver cancer. Based on this, the researchers hypothesized that mice lacking Arid1a would develop liver damage and, eventually, liver cancer. They were surprised when the opposite proved to be the case – no liver damage occurred. In fact, livers of the Arid1a-deficient mice regenerated faster and appeared to recover better.

“The livers were resistant to tissue damage and healed better, which are two good things – like playing offense and defense at the same time,” said Dr. Zhu, assistant professor in the CRI and of pediatrics and internal medicine. “These results opened up a whole new avenue of investigation for us, and through that investigation, we found a new function for this gene.” This raised the possibility that there are mechanisms that both promote tissue regeneration and inhibit the development of cancer.

The Zhu laboratory is currently funded by the Cancer Prevention and Research Institute of Texas (CPRIT) to develop a drug that would inhibit the function of Arid1a. The long-term hope is that such a drug will increase liver regeneration and inhibit the development of cancer.

GRANTS AND AWARDS

Two CRI faculty members were awarded prestigious grants in 2016. Dr. Hao Zhu was one of 10 researchers in the nation to receive a Stand Up To Cancer grant. This grant is awarded to early-career scientists to support innovative, high-risk, high-reward projects in cancer research. Dr. Zhu is using this grant to fund research that explores the relationship between organ regeneration and cancer formation. The lab will study mice that have a defect in a gene called Arid1a, which protects against liver cancer and promotes liver regeneration.

In September, Dr. Ralph DeBerardinis was among 84 scientists from 43 U.S. institutions chosen as a Howard Hughes Medical Institute Faculty Scholar. The program, in its first year, awarded grants of $600,000 to $1.8 million over five years to each early-career scientist. The HHMI Faculty Scholars were selected for their potential to make unique contributions to their fields. Dr. DeBerardinis plans to use his grant to further his research in cancer metabolism.

 

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