Stem Cell Scientists Reconstruct Disease in a Dish; Gain Insight into Deadly Form of Bone Cancer

The life of someone with Li-Fraumeni Syndrome (LFS) is not a pleasant one. A rare genetic disorder that usually runs in families, this syndrome is characterized by heightened risk of developing cancer—multiple types of cancer—at a very young age.

People with LFS, as the syndrome is often called, are especially susceptible to osteosarcoma, a form of bone cancer that most often affects children. Despite numerous research advances, survival rates for this type of cancer have not improved in over 40 years.

shutterstock_142552177 But according to new research from Mount Sinai Hospital and School of Medicine, the prognosis for these patients may not be so dire in a few years.

Reporting today in the journal Cell, researchers describe how they used a revolutionary type of stem cell technology to recreate LFS in a dish and, in so doing, have uncovered the series of molecular triggers that cause people with LFS to have such high incidence of osteosarcoma.

The scientists, led by senior author Ihor Lemischka, utilized induced pluripotent stem cells, or iPSCs, to model LFS—and osteosarcoma—at the cellular level.

Discovered in 2006 by Japanese scientist Shinya Yamanaka, iPSC technology allows scientists to reprogram adult skin cells into embryonic-like stem cells, which can then be turned into virtually any cell in the body. In the case of a genetic disorder, such as LFS, scientists can transform skin cells from someone with the disorder into bone cells and grow them in the lab. These cells will then have the same genetic makeup as that of the original patient, thus creating a ‘disease in a dish.’ We have written often about these models being used for various diseases, particularly neurological ones, but not cancer.

“Our study is among the first to use induced pluripotent stem cells as the foundation of a model for cancer,” said lead author and Mount Sinai postdoctoral fellow Dung-Fang Lee in today’s press release.

The team’s research centered on the protein p53. P53 normally acts as a tumor suppressor, keeping cell divisions in check so as not to divide out of control and morph into early-stage tumors. Previous research had revealed that 70% of people with LFS have a specific mutation in the gene that encodes p53. Using this knowledge and with the help of the iPSC technology, the team shed much-needed light on a molecular link between LFS and bone cancer. According to Lee:

“This model, when combined with a rare genetic disease, revealed for the first time how a protein known to prevent tumor growth in most cases, p53, may instead drive bone cancer when genetic changes cause too much of it to be made in the wrong place.”

Specifically, the team discovered that the ultimate culprit of LFS bone cancer is an overactive p53 gene. Too much p53, it turns out, reduces the amount of another gene, called H19. This then leads to a decrease in the protein decorin. Decorin normally acts to help stem cells mature into healthy, bone-making cells, known as osteoblasts. Without it, the stem cells can’t mature. They instead divide over and over again, out of control, and ultimately cause the growth of dangerous tumors.

But those out of control cells can become a target for therapy, say researchers. In fact, the team found that artificially boosting H19 levels could have a positive effect.

“Our experiments showed that restoring H19 expression hindered by too much p53 restored “protective differentiation” of osteoblasts to counter events of tumor growth early on in bone cancer,” said Lemischka.

And, because mutations in p53 have been linked to other forms of bone cancer, the team is optimistic that these preliminary results will be able to guide treatment for bone cancer patients—whether they have LFS or not. Added Lemischka:

“The work has implications for the future treatment or prevention of LFS-associated osteosarcoma, and possibly for all forms of bone cancer driven by p53 mutations, with H19 and p53 established now as potential targets for future drugs.”

Learn more about how scientists are using stem cell technology to model disease in a dish in our special video series: Stem Cells In Your Face:

Cancer Cells Mimic Blood Vessels to Colonize the Body’s Farthest Reaches

Scientists at Cold Spring Harbor Laboratory have just uncovered the latest dirty trick in the cancer playbook—one that spurs the cancer cells to spread throughout the body and evade treatment. But importantly, they believe they may have found a way to counter it.

Reporting today in the journal Nature, Cold Spring Harbor researchers describe how tumor cells can form tubular networks that mimic blood vessels. It is this mimicry, the team argues, that plays a key role in helping the cancer spread throughout the body—and a significant hurdle to successfully treating the disease.

Two adjacent sections of a mouse breast tumor. Tissue at left is stained so that normal blood vessels can be seen (black arrow). Extending from these vessels are blood filled channels (green arrows). On the right, the tissue is stained for a fluorescent protein expressed by the tumor cells. Here, blood-filled channels are actually formed by tumor cells in a process known as vascular mimicry. [Credit: Hannon Lab, CSHL]

Two adjacent sections of a mouse breast tumor. Tissue at left is stained so that normal blood vessels can be seen (black arrow). Extending from these vessels are blood filled channels (green arrows). On the right, the tissue is stained for a fluorescent protein expressed by the tumor cells. Here, blood-filled channels are actually formed by tumor cells in a process known as vascular mimicry. [Credit: Hannon Lab, CSHL]

Using mouse models of breast cancer, the team—led by Simon Knott—identified this phenomenon, called ‘vascular mimicry,’ and revealed that two genes, called Serpine2 and Slpi, were driving it. Made up of tumor cells literally stacked together, these tubular networks allowed oxygen and other nutrients to reach far-flung tumor cells throughout the body. This kept the tumor cells healthy, and helped them spread.

In today’s press release, Knott explained his initial reactions to this critical discovery:

“It’s very neat to watch and see cells evolve to have these capacities, but on the other hand it’s really scary to think that these cells are sitting there in people doing this.”

In laboratory experiments, the team found that boosting levels of Serpin2 and Slpi boosted the cancer’s ability to build these networks. Conversely, shutting down these two genes appeared to do the opposite. Knott argues that targeting the proteins that these two genes produce, as a way of shutting them off, may be a winning strategy:

“Targeting them might provide therapeutic benefits,” said Knott, “but we’re not sure yet.”

Indeed, research efforts over the past decade or more have tried to curb the production of these tubular networks of tumor cells, but with limited success. These drugs, called angiogenesis inhibitors, may not have worked as well as originally hoped because the underlying mechanism that creates this vascular mimicry—namely the genes Serpin2 and Slpi—was not targeted. Postdoctoral researcher Elvin Wagenblast, the paper’s first author, thinks they might have more success now:

“Maybe by targeting angiogenesis and also vascular mimicry at the same time we might actually have a better benefit in the clinic in the long run.”

This strategy is ultimately the goal of the team, but much work remains. Their most immediate next steps are to understand the process by which tumor cells pass through these tubular networks and infiltrate new areas of the body. But armed with this new-found knowledge of vascular mimicry, these and other researchers may be well on their way to outsmarting cancer, at least some of the time.

Building a Better Needle: CIRM-Funded Invention Gets Cells Into Brain More Safely, Efficiently

If NASA’s billion dollar Mars rovers deployed a bunch of dollar store party balloons to cushion the moment of impact, the mission would fail miserably. Likewise, the many years and millions of dollars spent on developing a stem cell-based therapy could be all for naught if the delivery of those precious cells into patients used cheap, inefficient tools.

That’s the subject of a recent TV interview with George Yu, who is CEO of Accurexa, a company that is developing and commercializing a novel syringe and needle device that could dramatically improve the delivery of cell therapies to the brain. The device was invented by UCSF neurosurgeon Daniel Lim with the support of a CIRM Tools and Technologies grant.

“So [Dr. Lim] participated in a phase 1 trial a few years ago where he was asked to deliver stem cell[-derived cells] to the brain and he didn’t really have adequate tools to do that, “ Yu explained in his interview with the New York-based finance and business TV program, New to the Street.

“The company that manufactured the stem cells spent millions of dollars in research but then they gave [Dr. Lim] a syringe and a needle that literally costs a couple of dollars. When he used that syringe and needle, which is a straight needle and injected those cells into the brain he actually saw a substantial amount of cells coming to the surface of the brain, which we call reflux, and that’s the reason he said there must be something better than this. And he applied for a grant, he got funded, and he invented the device. “

Not only does the standard straight syringe and needle cause a loss of transplanted cells due to reflux it also requires multiple injections in order to properly distribute the cell therapy in the brain. And with each injection, healthy brain tissue is damaged and increases the risk of stroke.

The Branched Point Device allows a well distributed cell transplantation into the brain with just one injection site. (image credit: Stereotact Funct Neurosurg. 2013; 91(2): 92–103.)

The Branched Point Device allows a well distributed transplantation of cells into the brain with just one injection site. (image credit: Stereotact Funct Neurosurg. 2013; 91(2): 92–103.)

Lim’s invention, called a Branched Point Device, avoids both cell reflux and the need for multiple injections. Instead of coming straight out of the needle tip, the cells are delivered through an opening that’s positioned on the side of the needle. So rather than re-injecting the needle, it’s incrementally rotated to deliver the cells in a different direction. With the use of a catheter that pokes through the needle, the cells can be distributed around the needle at different depths in a radial pattern much like the branches of a tree.

Use of the device in clinical trials may soon become a reality based on Yu’s comments in the interview:

“We’ve mostly completed our testing and the design of the device and we’re in the late stage of preparing a 510k submission to the FDA. So we expect that to happen this year. And once it’s FDA approved we can potentially sell the device.”

And because CIRM funded the development of this invention, the State of California is entitled to share in licensing revenue arising from the invention. Better still, the use of the device in clinical trials could provide more consistent, reliable results and a faster path to approval for stem cell-based therapies for neurodegenerative diseases like Parkinson’s.

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.”

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.

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.

Conference provides critical connections between clinical projects and investors

Having a mission like CIRM’s, which calls on us to develop therapies for unmet medical needs, clearly means we cannot sit back and marvel at all the great projects we have in the pipeline. We have to deliver commercial products available to all patients in need. And that cannot be done without additional investors.

The Alliance for Regenerative Medicine (ARM) takes that maxim seriously as well. The international advocacy organization, of which CIRM was a founding member five years ago, will host its third annual RegenMed Investor Day in New York City next Wednesday March 25.
ARM-logo-sm
During the full-day event 32 companies will present their progress to a wide array of investors. Traditional venture capital investors will be represented alongside investors from institutions and multinational pharmaceutical giants.

The day will be rounded out with three panel discussions and two fireside chats with market research analysts, company CEOs and leading clinicians. The fireside chat during lunch will feature CIRM President and CEO Dr. C. Randall Mills who will talk about public-private partnerships making joint investments to bring therapies to patients, and how the revised work plan we call CIRM 2.0 will make it easier for companies to work together with CIRM to advance promising therapies.

Getting just the eleven projects CIRM is funding in clinical trials today through to commercial products will require a broad mix of funding partnerships. With our portfolio and that of the industry as a whole growing rapidly, conferences like this one are critical.