A pivotal protein leads to autoimmune inflammation of the central nervous system in a mouse model of multiple sclerosis (MS) and potentially captures a key element of the human disease.

Researchers found that Peli1 plays a central signaling role in experimental autoimmune encephalomyelitis (EAE) and reported their findings in an advance online publication at Nature Medicine.

"The major implication of discovering a signaling role for Peli1 in this animal model is that it might also be significant in the pathogenesis of MS," said senior author Shao-Cong Sun, Ph.D., professor in MD Anderson's Department of Immunology.

Microglia cells involved in multiple sclerosis

Peli1 activates immune cells called microglia that promote inflammation in the central nervous system in response to tissue damage or invasion by microbes, directing a T cell attack. Sun and colleagues found that Peli1 is heavily expressed in microglial cells and is central to an abnormal, damaging autoimmune response.

Microglia are known to be crucial to the initiation of MS, an immune system assault on nerve fibers called axons and on myelin, the protective sheath around the axons.

Peli1 also initiates the destruction of a protein that otherwise would inhibit inflammation.

The researchers show that Peli1 tells another molecule to mark the protective Traf3 protein for destruction by the cell's proteasome. Traf3 restrains the MAPK molecular pathway, which activates a variety of genes involved in inflammation and T cell response.

With Traf3 degraded in the microglia, MAPK is unleashed.

Sun said the team is studying the pathway in human multiple sclerosis to replicate their findings and explore the possibilities for potentially treating MS.

Additional information

MD Anderson news release

Nature Medicine paper

"Cancer is a complex and heterogeneous disease driven by gene mutations. As we enter the era of personalized medicine, the characterization of the cancer genome has begun and will continue to influence diagnostic and therapeutic decisions in the clinic."

So begins Timothy Heffernan, Ph.D., associate director of target discovery at the Institute for Applied Cancer Science (IACS), in an article discussing how cancer genome discoveries have led to recent successes in oncology drug development through the identification of genetic alterations known as driver mutations.

"The translation of genomic data into drug development endpoints requires coordinated integration across multiple scientific disciplines. Genomic technologies provide comprehensive lists of genes that are altered in human cancer. Sophisticated computational models and powerful data analytics prioritize genes with the strongest weight of genomic evidence," he notes.

"Subsequent functional studies in relevant disease models provide biological significance by identifying genes that confer a proliferative and/or survival advantage to cancer cells.  Lastly, deep biological exploration is required to provide a mechanistic understanding of the gene's cancer-relevant activity," Heffernan writes.

Systematic approaches to apply genomic data

Heffernan's article in the current issue of the Insights and Developments newsletter discusses the systematic approaches implemented at IACS to functionalize genomic data and identify novel therapeutic targets.

  MD Anderson scientists Jim Allison and Hagop Kantarjian, at left, and Guillermina Lozano and Gabriel Hortobagyi, at right, won four of 14 individual awards for senior scientists at the AAACR Annual Meeting 2013 in Washington, D.C.

Highlights

Scientists and clinicians from across MD Anderson presented their latest research findings at the AACR Annual Meeting 2013 in Washington, D.C. 

A record six scientists, from post-doctoral fellows to junior faculty to senior investigators, won awards at the meeting run by the American Association for Cancer Research, the oldest and largest organization dedicated to cancer research in the world.

By the numbers, MD Anderson faculty members, post-docs and graduate students presented (follow link to Advanced Search, type MD Anderson in institution box):

• 160 research posters in 152 poster sessions.
• 25 oral presentations or invited talks
• 10 educational sessions
• 4 lectures tied to major awards.

Highlighted work included research by Xifeng Wu, M.D., Ph.D., professor and chair of the Department of Epidemiology, showing that low bilirubin levels in the blood are a sign of high risk for lung cancer among male smokers.

Elsa Flores, Ph.D., associate professor in the Department of Biochemistry and Molecular Biology, Her presentations included one that shows p63 and p73 can provide back-up tumor suppression when their more famous sibling, p53, is inactivated.  However, they also need to be protected from themselves or they might shut down all three tumor-blocking genes.

Ellen Gritz, Ph.D., chair and professor of the Department of Behavioral Sciences, co-authored a new AACR statement urging physicians to more closely monitor their patients' tobacco use and to provide smoking cessation information during clinical visits. 

The first of six awards to scientists at The University of Texas MD Anderson Cancer Center at this year's AACR Annual Meeting 2013 went to Guillermina "Gigi" Lozano, Ph.D., chair and professor in the Department of Genetics.

LozanoSaturday received the 16^th annual Women in Cancer Research Charlotte Friend Memorial Lectureship awarded by The American Association for Cancer Research (AACR), recognizing her contributions to the field of cancer research and the advancement of women in science.

Lozano delivered her award lecture, "Activities of Mutant p53 Proteins in Cancer," Saturday evening.

Expert on tumor-suppressor p53

Lozano presented her research showing that the chemotherapy drug doxorubicin is more effective against breast cancer with mutant p53 rather than normal p53. 

By Sarah Adai

Actin is a protein that has been long known to work by linking itself into chains to form filaments. Providing rigidity to the cell, actin filaments are involved in a host of processes including muscle contraction, cell mobility and cell division. The protein does this job outside of the nucleus, in the cytoplasm.

When actin was first discovered in the cell's nucleus several decades ago, it was dismissed as a contaminant. But since then a growing list of studies have supported a nuclear role for the protein, and scientists have been stumped as to what exactly it's doing there.

At long last, one of actin's key nuclear functions was uncovered. The study was published this week in the Journal Nature Structural & Molecular Biology.

Senior author of the study Xuetong "Snow" Shen, Ph.D., associate professor in The University of Texas MD Anderson Cancer Center Department of Molecular Carcinogenesis, developed a unique model system to nail down actin's function in the nucleus: the actin-containing INO80 chromatin remodeling complex in yeast cells.

"Our model system opened up a new opportunity to look in depth at the function of nuclear actin as it relates to gene regulation, genome stability, and ultimately cancer," Snow said.

The authors found that a mutant form of actin impairs the ability of INO80 to function correctly, implicating nuclear actin in the process of chromatin remodeling - a mechanism that helps regulate the expression of genes.

Cancer studies have increasingly focused on chromatin -- the intertwined proteins and DNA that are packaged into chromosomes -- because of its ability to regulate genes important for either activating or inhibiting tumorigenesis.

Surprisingly, Shen's lab found that actin inside the INO80 complex is arranged in such a way that it can't link up with itself to form filaments. Instead, the protein functions singly, as a monomer.

"Our study challenges the dogma that actin functions through polymerization, revealing a novel and likely a fundamental mechanism for monomeric nuclear actin," Shen said.

Paper: http://www.nature.com/nsmb/journal/vaop/ncurrent/full/nsmb.2529.html

News Release:
http://www.mdanderson.org/newsroom/news-releases/2013/nuclear-life-of-actin.html

For years, scientists have crafted vaccines designed to treat cancer, rather than to prevent it, by priming the immune system to track down and kill tumors.

They identify antigens - distinctive targets - on tumors, combine them with substances (adjuvants) to enhance immune response, and then inject the vaccine to treat a given cancer.

A frustrating pattern emerged, says Willem Overwijk, Ph.D. associate professor in MD Anderson's Department of Melanoma Medical Oncology.  In both mouse experiments and human clinical trials, the vaccines created abundant T cells specialized to find the antigen and destroy cells that have it.

These T cells were easily observed in the bloodstream, yet there was little or no effect on tumors in the vast majority of cases.

Overwijk and colleagues decided to focus their attention on potential problems in the vaccine itself.  What they found, reported this week in Nature Medicine, could profoundly alter vaccine design and effectiveness.

"We discovered that only a few T cells actually get to the tumor, while many more are stuck or double back to the vaccination site," Overwijk says.

Smoking remains the leading cause of preventable illness and death in the United States, so the health benefits of quitting are substantial. The majority of smokers are motivated to quit and more than half of all smokers attempt to quit each year. Sadly, only a small minority succeeds.

Researchers at MD Anderson are working to change this by changing the culture of how they reach self-admitted smokers with a new approach aimed at connecting through family practice clinics.

A collaboration involving MD Anderson researchers, the Texas Quitline and Kelsey-Seybold Clinics targeted smokers and their enrollment in tobacco treatment programs by directly connecting smokers with cessation quit lines.

Ask-Advise-Connect

Ask-Advise-Connect, a new approach designed to efficiently link smokers with cessation treatment, showed a significant increase in tobacco treatment enrollment by smokers who were directly contacted by quit line staff, according to results published online today in JAMA Internal Medicine. 

JAMA published a video interview Feb. 27 with study principal investigator Jennifer Irvin Vidrine, Ph.D., associate professor in the Department of Health Disparities Research at MD Anderson.

By William Fitzgerald

Gordon Mills, M.D., Ph.D., recalls a proposal he wrote 18 years ago detailing the concept of personalized cancer therapy and its potential impact. Today, that idea is no longer a proposal, but a reality, and it's about to get a boost.

Under a new and innovative institutional protocol called Clearing House, which started in March 2012, scientists are delving deeper into the biology of patients' tumors, with hopes of identifying specific genetic markers and prescribing therapies to attack those markers directly.

Funda Meric-Bernstam, M.D., professor in MD Anderson's Department of Surgical Oncology, and Mills, professor and chair of the institution's Department of Systems Biology, are leading the effort that will test up to 200 genes known to influence cancer in patients with aggressive or recurring disease.

"In the first year, we'll have sequenced the genes of far more than 1,000 MD Anderson patients and are targeting to have more than 3,000 by the second year," Meric-Bernstam says. "This will accelerate our discovery approaches, and we can develop new clinical trials, in which we already have patients pre-identified to enroll."

While the research began with solid tumors, the Clearing House protocol has expanded to all diseases that have ongoing genomically selected trials, Meric-Bernstam says.

Mills is co-director of MD Anderson's Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy and Meric-Bernstam is medical director of the institute.