As you probably know by now – May is National Cancer Research Month, and this is the second post in our blog series to profile cancer research programs underway at Sanford-Burnham. This week, we review a few of the programs that focus on a malfunctioning signaling process in cells called “signal transduction.” Signal transduction occurs when a molecule outside of a cell activates a receptor on the cell, triggering a response inside. This vital process drives a variety of functions, including how a cell senses and responds to environmental change and communicates with other cells. When signal transduction pathways malfunction, a variety of diseases can arise, including cancer.
The scientists of our NCI-designated Cancer Center
May is National Cancer Research Month
May is National Cancer Research Month, so we thought we’d highlight exciting cancer research underway at Sanford-Burnham. Today, we focus on a few of the strategies our researchers are pursuing to better understand the pathologies of cancer tumors—and stop them in their tracks.
Dr. Towler (left) with his team of scientists at his Lake Nona lab.
The hardening of arteries is a hallmark of atherosclerosis, an often deadly disease in which plaques, excessive connective tissue, and other changes build up inside vessel walls and squeeze off the flow of oxygen-rich blood throughout the body. Now, researchers at our Diabetes and Obesity Research Center have described the molecular and cellular pathway that leads to this hardening of the arteries—and zeroed in on a particularly destructive protein called Dkk1.
Their study was published online today by Arteriosclerosis, Thrombosis, and Vascular Biology. The findings suggest that the development of drug therapies to selectively inhibit endothelial Dkk1 signaling may help limit arteriosclerotic disease.
Prostate cancer cells expressing a mutant form of c-Myc that cannot be altered by PKCzeta (left) are more aggressive and more invasive than prostate cancer cells in which PKCzeta is able to keep tabs on c-Myc (right).
The enzyme PKCζ acts as a tumor suppressor by keeping the pro-tumor c-Myc gene in check, in both mice and humans.
Researchers have identified how an enzyme called PKCζ suppresses prostate tumor formation. The finding, which also describes a molecular chain of events that controls cell growth and metastasis, could lead to novel ways to control disease progression.
Sanford-Burnham Professors Jorge Moscat, Ph.D., and Maria Diaz-Meco, Ph.D. co-authored a study on p62's role in fat metabolism
Sanford-Burnham researchers show that protein p62 balances metabolism in fat tissue—making it an attractive target for anti-obesity therapies
In many cases, obesity is caused by more than just overeating and a lack of exercise. Something in the body goes haywire, causing it to store more fat and burn less energy. But what is it? Sanford-Burnham researchers have a new theory—a protein called p62. According to a study the team published December 21 in the Journal of Clinical Investigation, when p62 is missing in fat tissue, the body’s metabolic balance shifts—inhibiting “good” brown fat, while favoring “bad” white fat. These findings indicate that p62 might make a promising target for new therapies aimed at curbing obesity.
“Without p62 you’re making lots of fat but not burning energy, and the body thinks it needs to store energy,” said Jorge Moscat, Ph.D., Sanford-Burnham professor. “It’s a double whammy.” Moscat led the study with collaborators at Helmholtz Zentrum München in Germany and the University of Cincinnati.
Drug-like chemical compound LTV-1 (foreground) blocks the action of mutant LYP protein in human immune cells, providing a potential new therapeutic for autoimmune diseases.
New insight into mechanisms behind autoimmune diseases suggests a potential therapy
Originally published March 18, 2012
Autoimmune diseases, such as Type I diabetes and rheumatoid arthritis, are caused by an immune system gone haywire, where the body’s defense system assaults and destroys healthy tissues. A mutant form of a protein called LYP has been implicated in multiple autoimmune diseases, but the precise molecular pathway involved has been unknown. Now, in a paper published March 18 in Nature Chemical Biology, Sanford-Burnham researchers show how the errant form of LYP can disrupt the immune system. In doing so, they also found a potential new therapy for autoimmune diseases—a chemical compound that appears to inhibit this mutant protein.
![Breast tumor (blue) surrounded by blood vessels (red) [Image provided by Dr. William Stallcup]](http://beaker.sanfordburnham.org/wp-content/uploads/2012/10/breast-tumor_Stallcup1.jpg)
Breast tumor (blue) surrounded by blood vessels (red) [Image provided by Dr. William Stallcup]
What is breast cancer?
Breast cancer is the second most common type of cancer in women. In 2007 (the most recent year for which data is available), 202,964 women in the U.S. were diagnosed with breast cancer and 40,598 women died from the disease, according to the CDC. Approximately 12 percent of women in the general population will develop breast cancer sometime during their lives.
The most common types of breast cancer include ductal carcinoma, which begins in the cells that line the milk ducts of the breast, and lobular ductal carcinoma, which originates in the breast lobes.
A variety of genetic and environmental influences can increase a person’s risk of breast cancer. However, some breast cancers are associated with inherited mutations in a few specific genes. The best known are mutations in the genes BRCA1 and BRCA2 (BRCA stands for breast cancer susceptibility gene), which account for five to 10 percent of all breast cancer cases.
Depending on the type of breast cancer and its progression, treatments can include surgery, chemotherapy, radiation therapy, hormone therapy, or targeted therapy aimed specifically at disrupting the molecular underpinnings of the disease.
Breast cancer research at Sanford-Burnham
Sanford-Burnham is home to one of just seven National Cancer Institute (NCI)-designated basic cancer centers in the United States. Researchers in this center aim to preempt cancer before it develops, detect the disease at its earliest point, and eliminate its spread.
Historically, our scientists have made seminal contributions to breast cancer. Kristiina Vuori, M.D., Ph.D., now director of Sanford-Burnham’s Cancer Center, and others published early findings on cellular communication networks in breast cancer cells. John C. Reed, M.D., Ph.D., now Sanford-Burnham’s CEO, and his laboratory made seminal contributions to the understanding of how certain proteins direct programmed cell death (a process called apoptosis) in breast cancer cells and how these proteins allow breast tumors to resist chemotherapy.
While many researchers in Sanford-Burnham’s Cancer Center study cellular growth and lifespan—work that impacts almost every type of cancer—our scientists are also pursuing several strategies for finding new treatments that specifically target breast cancer.
Here are a few current breast cancer studies at Sanford-Burnham:
To survive, tumors need blood supply to provide them with nutrients and oxygen. To get that supply, cancer cells stimulate new blood vessel growth—a process called tumor angiogenesis. Many attempts have been made to inhibit this process as a means to choke off tumors. But tumor angiogenesis can be sloppy, resulting in immature and malformed blood vessels. Since anti-cancer drugs are carried to tumors by the bloodstream, abnormal blood vessel development also hampers delivery. What if, rather than putting a stop to angiogenesis, we could help tumor blood vessels mature more completely, so tumor-killing therapies could more effectively reach their targets? This counterintuitive concept was proposed several years ago, but researchers lacked a way to do it. Now, in a paper published August 14 in the journal Cancer Cell, Sanford-Burnham researchers found a molecule that promotes the tumor vessel maturation process—a discovery that might provide a method for improving cancer drug delivery.
“Our finding suggests that an ability to regulate this molecule could allow us to solve various problems caused by blood vessel abnormalities, including inefficient drug delivery to tumors,” said Masanobu Komatsu, Ph.D., associate professor at Sanford-Burnham and senior author of the study.
Sharon Schendel, Ph.D., former postdoctoral researcher at Sanford-Burnham and head of the Biochemical Journal's U.S. editorial office
How cells traffic nutrients and wage immune responses, how they repair themselves and self-destruct to save their neighbors, how they guard against disease and proliferate in the developing organism – it all comes down to a complex network of biochemical signals and how they’re regulated from moment to moment and cell to cell. Understanding the intricate genetic and chemical pathways inside a cell can help biologists and medical professionals better understand how to pinpoint where signaling has gone haywire, diagnose the onset of disease early, and develop and administer targeted therapeutic drugs.
Cell signaling and regulation was the topic of a symposium on March 22 at Sanford-Burnham’s La Jolla campus, where the sponsor of the meeting, the Biochemical Journal, a publication of the British Biochemical Society, has had its U.S. editorial offices since 2001. Discussions at the symposium, which focused on cell signaling and regulation as it relates to cancer, featured talks from eight Biochemical Journal editorial board members, as well as researchers John Reed and Sara Courtneidge from Sanford-Burnham, and Tony Hunter from the nearby Salk Institute
Drug-like chemical compound LTV-1 (foreground) blocks the action of mutant LYP protein in human immune cells, providing a potential new therapeutic for autoimmune diseases.
Autoimmune diseases, such as Type I diabetes and rheumatoid arthritis, are caused by an immune system gone haywire, where the body’s defense system assaults and destroys healthy tissues. A mutant form of a protein called LYP has been implicated in multiple autoimmune diseases, but the precise molecular pathway involved has been unknown. Now, in a paper published March 18 in Nature Chemical Biology, Sanford-Burnham researchers show how the errant form of LYP can disrupt the immune system. In doing so, they also found a potential new therapy for autoimmune diseases—a chemical compound that appears to inhibit this mutant protein.
Sumit Chanda, Ph.D.
In a healthy immune system, invading pathogens trigger a cascade of alerts and responses to fight off the infection. Sensors called toll-like receptors, or TLRs, act as one of the first lines of defense. Two of these sensors, known as TLR7 and TLR9, specifically recognize and respond to microbial RNA and DNA, respectively. But what determines how these TLRs get where they need to be and sound the alarm for pathogen infection? To answer this question, a team led by Sanford-Burnham’s Sumit Chanda, Ph.D. and colleagues used a technique known as RNA interference (RNAi) to silence each gene in the human genome one by one. In doing so, they were able to determine which genes are crucial for TLR7 and TLR9 functions and which are dispensable. In their study, published March 14 in Cell Host & Microbe, the team identified 190 proteins that contribute to our ability to detect and respond to microbial infection. These findings could help scientists develop new strategies to manipulate immune responses for treatment of autoimmune disorders and microbial infections.
Cerebellar stem cells engineered to express Myc and mutant p53 (shown here) give rise to aggressive tumors that resemble a particularly malignant form of human medulloblastoma, providing a new model that will help scientists develop more effective therapies for this disease.
Children with a devastating brain cancer called medulloblastoma develop tumors in a region of the brain called the cerebellum, which plays an important role in motor control. Seventy-five percent of children with the disease survive after aggressive surgery, radiation, and chemotherapy—but side effects can be severe, leading to cognitive deficits, endocrine disorders, and the development of other cancers later in life.
Sanford-Burnham scientists have now developed a new mouse model for studying medulloblastoma. The animal model mimics the deadliest of four subtypes of the human disease, a tumor that is triggered by elevated levels of a gene known as Myc. The study, published February 13 in the journal Cancer Cell, also suggests a potential strategy for inhibiting the growth of this tumor type. This achievement marks an important milestone toward personalized therapies tailored to a specific type of medulloblastoma.
“Being able to use an animal model as a tool to test treatments has been very valuable in medulloblastoma, as in other types of tumors. But for Myc-associated tumors, that hasn’t been an option because there hasn’t been a model of the disease. This is the first step to developing therapies for this type of tumor,” said Robert Wechsler-Reya, Ph.D., director of the Tumor Development Program in Sanford-Burnham’s National Cancer Institute-designated Cancer Center, member of the Sanford Consortium for Regenerative Medicine, and senior author of the study.
Calorie-burning brown fat (shown here) gets a boost from natriuretic peptides in the heart
It’s well known that exercising reduces body weight because it draws on fat stores that muscle can burn as fuel. But a new study at Sanford-Burnham suggests that the heart also plays a role in breaking down fat. In their study, published February 6 in the Journal of Clinical Investigation, Sheila Collins, Ph.D. and colleagues detail how hormones released by the heart stimulate fat cell metabolism. These hormones turn on a molecular mechanism similar to what’s activated when the body is exposed to cold and burns fat to generate heat. This study adds another dimension to our understanding of how the body regulates fat tissue and may someday lead to new ways to manipulate the process with drugs to reduce weight in obese patients or maintain it in individuals who experience pathological weight loss during chronic heart failure.
“Exercise is always going to raise your blood pressure some, so there’s the potential that these heart hormones—called cardiac natriuretic peptides—are being released and contributing to the breakdown of fats,” said Collins, professor in the Diabetes and Obesity Research Center at Sanford-Burnham’s Lake Nona campus in Orlando and senior author of the study. “Over a period of time, natriuretic peptides could also be leading to an increase in the numbers of brown fat cells, which we know are very important for protection against diet-induced obesity, at least in laboratory experiments.”
Chao-Shun Yang, graduate student in Dr. Tariq Rana's lab and first author of the study
Many research labs around the world are focused on finding the most effective ways to reprogram an adult cell (a skin cell, for example) into induced pluripotent stem cells (iPSCs)—that is, cells that have the ability to develop into other tissues in the body. These cells not only offer researchers powerful tools to study a particular patient’s individual disease, but they have the potential to therapeutically replace diseased or damaged tissue in the patient from whom the cells originated.
Most experiments to reprogram adult cells employ viruses as vehicles to carry four particular genes—called reprogramming factors—into the nucleus of a cell. But genetic engineering carries its own risks, including the chance that these cells will continue replicating, eventually forming a tumor. What’s more, scientists are not exactly sure what the reprogramming factors do, on the molecular level, to promote the generation of iPSCs.
Could there be a safer and more predictable way to alter the expression of genes in cells, thereby reprogramming their DNA so they revert to their earlier, more malleable state?
Dr. Masanobu Komatsu, associate professor at Sanford-Burnham
If you have cancer today, finding out how advanced the tumor has become often requires an invasive biopsy and precious time to prepare and analyze cancerous cells in the lab. Sanford-Burnham’s Dr. Masanobu Komatsu sees another way to rapidly diagnose what’s happening deep inside you.
Someday, he envisions, your doctor will simply administer a solution of nanoparticles that contain a fluorescent dye and a chemical address that helps them home to the tumor cells in your body. The dye will have unique physical properties that enable imaging inside the tissue. A laser device will then beam infrared light into the tumor site, exciting the fluorescent dye that has accumulated in the cancer cells. A computer monitor will display an image of the tumor with cell-by-cell resolution.