Breast Cancer Tumors Recruit Immune Cells to the Dark Side

We rely on our immune system to stave off all classes of disease—but what happens when the very system responsible for keeping us healthy turns to the dark side? In new research published today, scientists uncover new evidence that reveals how breast cancer tumors can actually recruit immune cells to spur the spread of disease.

Some forms of breast cancer tumors can actually turn the body's own immune system against itself.

Some forms of breast cancer tumors can actually turn the body’s own immune system against itself.

Breast cancer is one of the most common cancers, and if caught early, is highly treatable. In fact, the majority of deaths from breast cancer occur because the disease has been caught too late, having already spread to other parts of the body, a process called ‘metastasis.’ Recently, scientists discovered that women who have a heightened number of a particular type of immune cells, called ‘neutrophils,’ in their blood stream have a higher chance of their breast cancer metastasizing to other tissues. But they couldn’t figure out why.

Enter Karin de Visser, and her team at the Netherlands Cancer Institute, who announce today in the journal Nature the precise link between neutrophil immune cells and breast cancer metastasis.

They found that some types of breast tumors are particularly nefarious, sending out signals to the person’s immune system to speed up their production of neutrophils. And then they instruct these newly activated neutrophils to go rogue.

Rather than attack the tumor, these neutrophils turn on the immune system. They especially focus their efforts at blocking T cells—the type of immune cells whose job is normally to target and attack cancer cells. Further examination in mouse models of breast cancer revealed a particular protein, called interleukin 17 (or IL17) played a key role in this process. As Visser explained in today’s news release:

“We saw in our experiments that IL17 is crucial for the increased production of neutrophils. And not only that, it turns out that this is also the molecule that changes the behavior of the neutrophils, causing them to become T cell inhibitory.”

The solution then, was clear: block the connection, or pathway, between IL17 and neutrophils, and you can thwart the tumor’s efforts. And when Visser and her team, including first author and postdoctoral researcher Seth Coffelt, did this they saw a significant improvement. When the IL17-neutrophil pathway was blocked in the mouse models, the tumors failed to spread at the same rate.

“What’s notable is that blocking the IL17-neutrophil route prevented the development of metastases, but did not affect the primary tumor,” Visser added. “So this could be a promising strategy to prevent the tumor from spreading.”

The researchers are cautious about focusing their efforts on blocking neutrophils, however, as these cells are in and of themselves important to stave off infections. A breast cancer patient with neutrophil levels that were too low would be at risk for developing a whole host of infections from dangerous pathogens. As such, the research team argues that focusing on ways to block IL17 is the best option.

Just last month, the FDA approved an anti-IL17 based therapy to treat psoriasis. This therapy, or others like it, could be harnessed to treat aggressive breast cancers. Says Visser:

“It would be very interesting to investigate whether these already existing drugs are beneficial for breast cancer patients. It may be possible to turn these traitors of the immune system back towards the good side and prevent their ability to promote breast cancer metastasis.”

Stem cell stories that caught our eye; creating bone, turning data into sound, cord blood and path of a stem cell star

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

A better ratio of bone to fat
. Most of us at any age would prefer a little less fat and older folks, particularly ones plagued by the bone loss of osteoporosis, could use a bit more bone. Since both types of tissues come from mesenchymal stem cells (MSCs) a team at the University of Miami decided to look for chemical triggers that tells those stem cells whether to become fat or bone.

They found an enzyme that seems to do just that. In mice that were born with a mutation in the gene for that enzyme they saw increased bone growth, less fat production and a leaner body mass. HealthCanal picked up the university’s press release that quoted the leader of the team Joshua Hare:

“The production of bone could have a profound effect on the quality of life for the aging population.”

He goes on to note that there are many hurdles to cross before this becomes a therapeutic reality, but the current work points to lots of potential.

Path to becoming a star stem cell scientist. D, the city magazine for Dallas, published a lengthy—nearly 4,000-word—feature on Sean Morrison, one of the undisputed leaders of our field. While it starts out talking about his latest role of creating a multi-pronged center for innovation at

Sean Morrison

Sean Morrison

Children’s Medical Center Dallas and UT Southwestern, it spends most of its words on how he got there.

It’s fun reading how someone gets into a field as new as stem cell science and what keeps them in the field. Initially, for him it seems to originate from an immense curiosity about what was not known about the powerful little stem cells.

“Fifteen years ago, there was nothing known at the molecular level about how stem cells replicate. And I really felt it was a fundamental question in biology to understand. It was a question that was central to a lot of important issues, because the ability of stem cells to self-renew is critical to form your tissues throughout development, to maintain your tissues throughout adulthood.”

There is also a good retelling of Morrison’s role in the protracted and hard-fought battle to make embryonic stem cell research legal during his years in Michigan. He started working on the campaign to overturn the ban in 2006 and in 2008 the voters agreed. The article makes a compelling case for something I have advocated for years: scientists need to practice speaking for the public and get out and do it.

Turning stem cell data into sound. Interpreting scientific data through sound, sonification, is a bit trendy now. But the concept is quite old. Think of the Geiger counter and the speed of the click changing based on the level of radiation.

Researchers tend to consider sonification when dealing with large data sets that have some level of repetitive component. Following the differentiation of a large number of stem cells as they mature into different types of tissue could lend itself to the genre and a team at Cardiff University in Scotland reports they have succeeded. In doing just that.

HealthCanal picked up the university’s piece talking about the project. Unfortunately it does a very poor job of explaining how the process actually works. I did find this piece on ocean microbes that describes the concept of sonification of data pretty well.

Cord blood poised for greater use. I get very uncomfortable when friends ask for medical advice around stem cells. I usually try to give a lay of the land that comes short of direct advice. A common question centers on the value of paying the annual storage fees to freeze their baby’s cord blood. To which, I typically say that for current uses the value is marginal, but for the uses that could come in five to 10 years, it could be quite significant.

So, it was not surprising to read a headline on a Scientific American Blog last December reading “Vast Majority of Life-Saving Cord Blood Sits Unused.” But it was also fun to read a well-documented counter point guest blog on the site this morning by our former President, Alan Trounson. He suggested a better headline would be: “Vast Majority of Life-Saving Cord Blood Sits Poised for Discovery.”

He details how cord blood has become a valuable research tool and lists some of the FDA-approved clinical trials that could greatly expand the indication of cord blood therapy. While some of those trials will likely produce negative results, some will succeed and they all will start to show how to turn those frozen vials into a more valuable resource.

Why TED Talks are ChildX’s Play

When the TED (Technology, Entertainment, Design) talks began in 1984 they were intended to be a one-off event. So much for that idea! Today they are a global event, with TED-sponsored conferences held everywhere from Scotland to Tanzania and India. They have also spawned a mini-industry of copycat events. Well, their slogan is “Ideas Worth Spreading” so in a way they only have themselves to blame for having such a great idea.

Dr. Maria Grazia Roncarolo

Dr. Maria Grazia Roncarolo

The latest place for that idea to take root is Stanford, which is holding a TED-style event focused on critical issues facing child and maternal health. The event – April 2nd and 3rd at Stanford – is called ChildX where x = medicine + technology + innovative treatment + wellbeing. ChildX will bring together some of the leading experts in the field for a series of thoughtful, powerful presentations on the biggest problems facing child and maternal health, and the most exciting research aimed at resolving those problems. One of the main tracks during the two-day event is a section on stem cell and gene therapy. It will raise a number of key questions including:

  • What advances have occurred to enable these therapies to move from science fiction less than a decade ago to the promise of next generation transformative therapeutics?
  • In coming years, how will these therapies allow children with presently incurable diseases to become children living free of disease and reaching their maximum potential?

The moderator for that discussion is Dr. Maria Grazia Roncarolo, and you can hear her talking about the most recent advances in the clinical use of stem cell and gene therapies on this podcast. Anytime you get a chance to hear some of the most compelling speakers in their field talk about exciting innovations that could shape the future, it’s worth taking the time to listen.

Goodnight, Stem Cells: How Well Rested Cells Keep Us Healthy

Plenty of studies show that a lack of sleep is nothing but bad news and can contribute to a whole host of health problems like heart disease, poor memory, high blood pressure and obesity.

HSCs_Sleeping_graphic100x100

Even stem cells need rest to stay healthy

In a sense, the same holds true for the stem cells in our body. In response to injury, adult stem cells go to work by dividing and specializing into the cells needed to heal specific tissues and organs. But they also need to rest for long-lasting health. Each cell division carries a risk of introducing DNA mutations—and with it, a risk for cancer. Too much cell division can also deplete the stem cell supply, crippling the healing process. So it’s just as important for the stem cells to assume an inactive, or quiescent, state to maintain their ability to mend the body. Blood stem cells for instance are mostly quiescent and only divide about every two months to renew their reserves.

Even though the importance of this balance is well documented, exactly how it’s achieved is not well understood; that is, until now. Earlier this week, a CIRM-funded research team from The Scripps Research Institute (TSRI) reported on the identification of an enzyme that’s key in controlling the work-rest balance in blood stem cells, also called hematopoietic stem cells (HSCs). Their study, published in the journal Blood, could point the way to drugs that treat anemias, blood cancers, and other blood disorders.

Previous studies in other cell types suggested that this key enzyme, called ItpkB, might play a role in promoting a rested state in HSCs. Senior author Karsten Sauer explained their reasoning for focusing on the enzyme in a press release:

“What made ItpkB an attractive protein to study is that it can dampen activating signaling in other cells. We hypothesized that ItpkB might do the same in HSCs to keep them at rest. Moreover, ItpkB is an enzyme whose function can be controlled by small molecules. This might facilitate drug development if our hypothesis were true.”

Senior author Karsten Sauer is an associate professor at The Scripps Research Institute.

Senior author Karsten Sauer is an associate professor at The Scripps Research Institute.

To test their hypothesis, the team studied HSCs in mice that completely lacked ItpkB. Sure enough, without ItpkB the HSCs got stuck in the “on” position and continually multiplied until the supply of HSCs stores in the bone marrow were exhausted. Without these stem cells, the mice could no longer produce red blood cells, which deliver oxygen to the body or white blood cells, which fight off infection. As a result the animals died due to severe anemia and bone marrow failure. Sauer used a great analogy to describe the result:

“It’s like a car—you need to hit the gas pedal to get some activity, but if you hit it too hard, you can crash into a wall. ItpkB is that spring that prevents you from pushing the pedal all the way through.”

With this new understanding of how balancing stem cell activation and deactivation works, Sauer and his team have their sights set on human therapies:

“If we can show that ItpkB also keeps human HSCs healthy, this could open avenues to target ItpkB to improve HSC function in bone marrow failure syndromes and immunodeficiencies or to increase the success rates of HSC transplantation therapies for leukemias and lymphomas.”

The best tools to be the best advocate

It’s hard to do a good job if you don’t have the right tools. And that doesn’t just apply to fixing things around the house, it applies to all aspects of life. So, in launching our new website this week we didn’t just want to provide visitors to the site with a more enjoyable and engaging experience – though we hope we have done that – we also wanted to provide a more informative and helpful experience. That’s why we have created a whole new section call the Patient Advocate Toolbox. shutterstock_150769385

The goal of the Toolbox is simple; to give patients and patient advocates help in learning the skills they need to be as effective as possible about raising awareness for their particular cause.

As an advocate for a disease or condition you may be asked to speak at public events, to be part of a panel discussion at a conference, or to do an interview with a reporter. Each of those requires a particular set of skills, in areas that many of us may have little, if any, experience in.

That’s where the Toolbox comes in. Each section deals with a different opportunity for you to share your story and raise awareness about your cause.

In the section on “Media Interviews”, for example, we walk you through the things you need to think about as you prepare to talk to a reporter; the questions to ask ahead of time, how to prepare a series of key messages, even how to dress if you are going to be on TV. The idea is to break down some of the mystique surrounding the interview, to let you know what to expect and to help you prepare as fully as possible.

If you are going to be asked questions about stem cell research there’s a section in the Toolbox called “Jargon-Free Glossary” that translates scientific terms into every-day English, so you can talk about this work in a way that anyone can understand.

There’s also a really wonderfully visual infographic on the things you need to know when thinking about taking part in a clinical trial. It lays out in simple, easy-to-follow steps the questions you should ask, the potential benefits and problems of being in a trial, including the risks of going overseas for unproven therapies.

The Toolbox is by no means an exhaustive list of all the things you will need to know to be an effective advocate, either for yourself or a friend or loved one, but it is a start.

We would love to hear from you on ways we can improve the content, on other elements that would be useful to include, on links to other sites that you think would be helpful to add. Our goal is to make this as comprehensive and useful as possible. Your support, your ideas and thoughts will help us do just that. If you have any comments please send them to info@cirm.ca.gov

Thomas Carlyle, the Scottish philosopher, once wrote: “Man is a tool-using animal. Without tools he is nothing, with tools he is all.” That’s why we want to give you the tools you need to be as effective as you can. Because the more powerful your voice, the more we all benefit.

CIRM Launches New and Improved Website

CIRM has experienced many exciting changes over the past year: we’ve welcomed a new president, revamped our blog and—perhaps most importantly—announced a radical overhaul in how we fund stem cell research with the launch of CIRM 2.0. That’s not even mentioning the 11 projects we are now funding in clinical trials.

And now, we’d like to announce our latest exciting change: we’ve given our website a facelift that reflects the new CIRM 2.0. Allow us to introduce you to the new digital home of California’s Stem Cell Agency:

CIRM Homepage

Our mission—accelerating stem cell treatments to patients with unmet medical needs—informs everything we do here at CIRM, and the redesign of our website is no different. In improving our site, we hope to better serve two important audiences who are critical in us achieving our mission:

  • Current and potential grantees from research institutions and industry; and
  • Patients, patient advocates and the public at large who are helping others understand how CIRM-funded scientists are turning stem cells into cures.

We are also using this opportunity to improve the way we are viewed on mobile devices. With up to 40 percent of our visitors coming to cirm.ca.gov via a smartphone or tablet, we wanted to create a superior mobile user experience—so that people can easily access the same content whether they are at home or on the go.

We began this project just a few short months ago, and are thankful for a stellar team of in-house staff and contractors who each dove in to lend a hand. We are especially grateful to Radiant, who worked with CIRM to develop an improved design and navigation.

CIRMnew_Logo_Orange_1300x533

As part of the process of updating the website we also took the opportunity to update our logo. The old logo was ten years old, an eternity in the age of the Internet. We wanted something that reflected our new streamlined approach to funding, something that was visually appealing and contemporary and something that immediately connected the viewer to who we are and what we do. We hope you like it.

So please, take a look around at the new cirm.ca.gov—we hope you enjoy using it as much as we enjoyed creating it for you. And of course if you have any thoughts or suggestions on how we can improve this even more we’d love to hear from you in the comments below.

Stem cell stories that caught our eye; cystic fibrosis, brain repair and Type 2 diabetes

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

“Organoids” screen for cystic fibrosis drugs
. Starting with iPS-type stem cells made by reprogramming skin cells from cystic fibrosis (CF) patients a team at the University of Cambridge in the U.K. created mini lungs in a dish. These organoids should provide a great tool for screening drugs to treat the disease.

The researchers pushed the stem cells to go through the early stages of embryo development and then on to become 3-D distal airway tissue, the part of the lung that processes gas exchange. They were able to use a florescent marker to show an aspect of the cells’ function that was different in cells from CF patients and those from normal individuals. When they treated the CF cells with a drug that is being tested in CF patients, they saw the function correct to the normal state.

Bioscience Technology
picked up the university’s press release about the work published in the journal Stem Cells and Development. It quotes the scientist who led the study, Nick Hannon, on the application of the new tool:

“We’re confident this process could be scaled up to enable us to screen tens of thousands of compounds and develop mini-lungs with other diseases such as lung cancer and idiopathic pulmonary fibrosis.”

To repair a brain knock its “pinky” down. A team at the University of California, San Francisco, has discovered a molecule that when it is shut down nerve stem cells can produce a whole lot more nerves. They call the molecule Pnky, named after the cartoon Pinky and the Brain.

Pinky_and_the_Brain_vol1Pkny belongs to a set of molecules known as long noncoding RNAs (lncRNAs), which researchers are finding are more abundant and more important than originally thought. The most familiar RNAs are the intermediary molecules between the DNA in our genes and the proteins that let our cells function. Initially, all the noncoding RNAs were thought to have no function, but in recent years many have been found to have critical roles in determining which genes are active. And Pnky seems to tamp down the activity of nerve stem cells. In a university press release picked up by HealthCanal Daniel Lim, the head researcher explained what happens when they shut down the gene:

“It is remarkable that when you take Pnky away, the stem cells produce many more neurons. These findings suggest that Pnky, and perhaps lncRNAs in general, could eventually have important applications in regenerative medicine and cancer treatment.”

Lim went onto explain the cancer connection. Since Pnky binds to a protein found in brain tumors, it might be involved in regulating the growth of brain tumors. A lot more work needs to happen before that hunch—or the use of Pnky blockers in brain injury—can lead to therapies, but this study certainly paints an intriguing path forward.

Stem cells and Type 2 diabetes. A few teams have succeeded in using stem cells to produce insulin-secreting tissue to correct Type 1 diabetes in animals, but it has been uncertain if the procedure would work for Type 2 diabetes. Type 1 is marked by a lack of insulin production, while resistance to the body’s own insulin, not lack of insulin, is the hallmark of type 2. A team at the University of British Columbia has new data showing stem cell therapy may indeed have a place in treating Type 2.

In mice fed a high fat diet until they developed the symptoms of Type 2 diabetes the stem cell-derived cells did help, but they did not fully correct the metabolism of the mice until they added one of the drugs commonly used to treat diabetes today. The drugs alone, also did not restore normal metabolism, which is often the case with human Type 2 diabetics.

The combination of drugs and cells improved the mice’s sugar metabolism, body weight and insulin sensitivity. The research appeared in the journal Stem Cell Reports and the University’s press release was picked up by several outlets including Fox News.

They transplanted cells from humans and even though the mice were immune suppressed, they took the added measure of protecting the cells in an encapsulation device. They noted that this would be required for use in humans and showing that it worked in mice would speed up any human trials. They also gave a shout out to the clinical trial CIRM funds at Viacyte, noting that since the Food and Drug Administration has already approved use of a similar device by Viacyte, the work might gain more rapid approval.

The eyes have it: a video guide to stem cells

We are visual creatures. Our eyes are essential tools in getting information to our brain to help us learn and understand. For example, visuals are processed about 60,000 times faster in the brain than text is, and some 60 percent of us are visual learners, meaning we respond better to visual information than to plain text.

ben paylorThat’s why a series of 8 videos, just completed by Ben Paylor and Mike Long at InfoShots, are so wonderful. They are fun, simple and engaging videos that help make some of the complex science around stem cells readily understandable thanks to the use of eye-catching animation and simple, everyday English.

The videos are short, all around one minute (less time than it takes to make a cup of tea). Each video has a single theme – ‘What is a stem cell”, “What is stem cell tourism” – and they are all masterful at walking you through different aspects of stem cell research.

The last video in the series is about neural stem cells, which is highly appropriate considering this is Brain Awareness Week, a worldwide celebration of the brain.

The videos are a reminder that the most effective communication is often the most direct, cutting through the clutter and getting to the heart of the subject. The beauty of these is that Ben and Mike are keen to share them with as many people as possible and have made them available to anyone who wants to watch them or use them as a teaching tool.

Finally, credit for the videos also has to go to the Canada’s Stem Cell Network and the Canadian Stem Cell Foundation, which helped fund them.

New understanding of the inner workings of our genetic tool kit should help us make smarter repairs

For young biology students the steps from genes to their function becomes a mantra: DNA makes RNA and RNA makes protein. But it is really not quite that simple. A few different types of RNA act along the path and we are now learning that the structure, or shape, of the individual RNA molecules affects their function.

Which genes succeed in producing their designated protein determines what the cell actually does—what kind of tissue it is and how well it performs the role it is assigned. Switching gene function on and off turns out to be quite complex with players among the molecules that are part of the backbone of DNA as well as the various forms of RNA. We have made great strides in the past decade in understanding the role of those DNA structural components, the so-called epigenetics, but still have major gaps in our understanding of the many roles of RNA.

DNA dogmaWith CIRM-funding, a team headed by Howard Chang at Stanford has gotten around a major hurdle in unlocking this complex issue. Like DNA, RNA is made up of various repeats of four molecules called bases. Prior to Chang’s work researchers could only track the structure of RNA associated with two of those bases. His team modified a commonly used bio-chemical tool called SHAPE to reveal the workings of all four RNA bases in living cells.

The team verified something that is increasingly being shown, static cells frozen in time a lab dish do not necessarily reflect what goes on in living cells. In this study those differences manifest in the structure of the RNA that determines what molecules are next to each other, which impacts their activity. After more than 2 billion measurements of more than 13,000 RNAs in the lab and in living cells, the team quantified those differences and showed how this molecular “folding” changes the function of the various RNAs.

They published the work, for which they used mouse embryonic stem cells, on-line today in Nature. In the closing paragraph of the journal article they speculate on the impact of the new ability to better understand the roles of RNA:

“In the future, viewing the RNA structurome when cells are exposed to different stimuli or genetic perturbations should revolutionize our understanding of gene regulation in biology and medicine.”

Since so many of the research projects that seek to reverse the course of disease try to change the genetic functioning of cells, this new understanding should be able to reduce the number of blind alleys scientist have to go down to get a desired result. It should allow the design of studies based on more logic and less chance, speeding the development of therapies.