Recently in Basic Science Research Category

The epidermal growth factor receptor (EGFR) often goes haywire in cancer, sending constant, urgent signals into a cell, telling it to grow and divide.

But in oxygen-starved conditions, EGFR also stifles production of tumor-suppressing microRNAs,  a team of scientists led by MD Anderson researchers reported online at the journal Nature.

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

  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

A key to the perils of endless injury repair, the molecular path from stress through a cancer-promoting gene to ovarian cancer progression, and signals by endothelial cells that strengthen  colorectal cancer are among recent discoveries by MD Anderson researchers.

By uncovering these new connections, scientists expose new potential targets for fibrosis, the lethal scarring of organs, and cancer.

Endothelial cells make cancer cells tougher, more dangerous 

"Cancer stem cells initiate and sustain tumor growth, promote metastasis and resistance to chemotherapy and have a variety of other attributes," says Lee Ellis, M.D., of MD Anderson's Department of Surgical Oncology. The blood vessels cells activate Notch signaling.  Drugs in  clinical trials attack Notch. 

News release and Cancer Cell paper

Stress hormone breaks dam, cancer-promoting flood follows

The hormone noradrenaline turns on the oncogene Src, which promotes ovarian cancer growth and spread through beta-adrenergic (ADRB) receptors expressed on tumor cells.

"When Src is triggered by stress, it works like a dam letting out water that causes a flood downstream. Src, like the dam, is a master regulator switch that causes a chain reaction in the cells," says Anil Sood, M.D., of the departments of gynecological medical oncology and cancer biology. One implication: beta blockers might work against ovarian cancer.

News release and Nature Communications paper

Protein plays pivotal role in scarring that destroys organs

When the body's wound-healing process gets endlessly turned on, the tissues that provide a scaffold for injury repair can destroy the kidneys, liver and lungs. This process, known as fibrosis, also is tightly tied to cancer.

"Fibrosis is wound-healing that never stops. The body thinks an injury exists when it doesn't, so it just keeps going, producing scars that clog an organ's system and destroy its functional tissue until it fails," says Raghu Kalluri, Ph.D., M.D., chair of the Department of Cancer Biology. Kalluri and colleagues identified the role of HE4 in promoting fibrosis. A test already approved for ovarian cancer detects HE4 levels in the blood.

News release and Nature Medicine paper

By Sharon Dent, Ph.D., David Johnson, Ph.D., and Sarah Adai

Chromatin, the intertwined histone proteins and DNA that are packaged into chromosomes, has long been recognized as a gatekeeper to the underlying DNA template.

While chromatin is typically on the receiving end of the cell's intricate signaling pathways - culminating in the regulation of gene expression - evidence is emerging to give chromatin a previously unrecognized role: as a dynamic participant that transmits received signals back to other proteins to effect changes in cellular responses.  

This week in the journal Cell, faculty from MD Anderson's Department of Molecular Carcinogenesis and Center for Cancer Epigenetics review a number of recent studies highlighting chromatin's role as both receiver and transmitter of signals in various cell functions.

Histone modifications: key players in chromatin signaling

Posttranslational modification of histones is one way that the cell regulates the packing and unpacking of chromatin, which in turn helps to determine whether a gene is activated or repressed.

When a crucial enzyme is dotted with targets that summon an attack by a cell's protein-destroying complex, another molecule comes to the rescue, blinding the attacker by wiping off the targets. 

The enzyme, called TRAF3,  survives to control a molecular network that's implicated in a variety of immune system-related diseases if left to its own devices.

University of Texas MD Anderson Cancer Center scientists identified TRAF3's savior and demonstrated how it works in a paper published online this week in Nature.

By discovering the role of OTUD7B as TRAF3's protector, Shao-Cong Sun, Ph.D., professor in MD Anderson's Department of Immunology, and colleagues filled an important gap in their understanding of a molecular pathway discovered in Sun's lab.

"Genetic defects or constant degradation of TRAF3 lead to the uncontrolled activity of what we call the non-canonical NF-kB pathway. This in turn, is associated with autoimmune diseases and lymphoid malignancies such as multiple myeloma and B cell lymphomas," Sun said. "Understanding how the degradation of TRAF3 is regulated is extremely important."

Cancer begins when a single cell goes haywire.  Now the keys to understanding that cell's transition to lethal tumor may be found in the unprecedented analysis of single tumor cells.

By isolating, capturing and then analyzing the genome of individual cells, Nicholas Navin, Ph.D., assistant professor in MD Anderson's Department of Genetics, proposes to identify the mutations that allow a primary tumor cell to escape into the bloodstream and then to establish a deadly colony in another organ.

Successfully analyzing differences in active mutations among single cells would help researchers understand, map and eventually block the lethal path to metastasis - the spread of the primary cancer to other organs.  Primary tumors are rarely lethal, Navin notes, but their genetic diversity from cell to cell hinders scientists' ability to understand metastasis.

The Damon Runyon Cancer Research Foundation will give Navin the opportunity to try his unique approach.  He is the Nadia's Gift Foundation Innovator, one of only seven 2013 Damon Runyon-Rachleff Innovation Awards announced earlier this month.

The foundation announcement notes the innovation awards are for "cancer research by exceptionally creative thinkers with "high-risk/high-reward" ideas who lack sufficient preliminary data to obtain traditional funding." Navin's approach "will have myriad clinical applications, which have prognostic value in predicting invasion, metastasis, survival and response to chemotherapy."

A protein that sneaks into the cell nucleus and sets off two separate cancer-promoting processes vital to the development of malignant brain tumors makes itself an enticing target for therapy.

Having exposed that dangerous behavior by pyruvate kinase M2 (PKM2) in a series of major publications, MD Anderson scientist Zhimin Lu, M.D., Ph.D., has uncovered a vulnerability that he thinks could turn the metabolic protein into "an Achilles' heel for cancer."

In a paper this week in Nature Cell Biology, Lu and colleagues identified a drug that inhibits growth of brain tumors in mice by thwarting PKM2.

Lu, an associate professor in MD Anderson's Department of Neuro-Oncology, and colleagues have discovered:

•        The cellular mechanism that overexpresses PKM2 in cancer cells.
•       The complex pathway that smuggles PKM2 into the cell nucleus.
•        How in the nucleus PKM2 activates genes involved in cell division and in a glucose metabolism pathway that nourishes brain tumors and other types of cancer called the Warburg effect.

"For tumors to form, PKM2 must get to the nucleus to activate genes involved in cell proliferation and the Warburg effect," Lu said. "If we can keep it out of the nucleus, we can block both of those cancer-promoting pathways."