Cancer Traps: A non-invasive way to biopsy tissue from cancer-tainted organs

Artistic render. Image credit: Steve Alvey, Michigan Engineering

Invasive procedures to biopsy tissue from cancer-tainted organs could be replaced by simply taking samples from a tiny “decoy” implanted just beneath the skin, University of Michigan researchers have demonstrated in mice.

These devices have a knack for attracting cancer cells traveling through the body. In fact, they can even pick up signs that cancer is preparing to spread, before cancer cells arrive.

“Biopsying an organ like the lung is a risky procedure that’s done only sparingly,” said Lonnie Shea, the William and Valerie Hall Chair of biomedical engineering at U-M. “We place these scaffolds right under the skin, so they’re readily accessible.”

The ease of access would also allow doctors to monitor the effectiveness of cancer treatments closer to real time.

The U-M team’s most recent work appears in Cancer Research, a publication of the American Association for Cancer Research.

Biopsies of the scaffold allowed researchers to analyze 635 genes present in the captured cancer cells. From these genes, the team identified ten that could predict whether a mouse was healthy, if it had a cancer that had not begun to spread yet, or if a cancer was present and had begun to spread. They could do that all without the need for an invasive biopsy of an organ.

The gene expression obtained at the scaffold had distinct patterns relative to cells from the blood, which are obtained through a technique known as liquid biopsy. These differences highlight that the tissue in these traps provides unique information that correlates with disease progression.

The researchers have demonstrated that the synthetic scaffolds work with multiple types of cancers in mice, including pancreatic cancer. They work by luring immune cells, which, in turn, attract cancer cells.

“When we started off, the idea was that we would biopsy the scaffold and look for tumor cells that had followed the immune cells there,” Shea said. “But we realized that by analyzing the immune cells that gather first, we can detect the cancer before it’s spreading.”

In treating cancer, early detection is key.

“Currently, early signs of metastasis can be difficult to detect,” said Jacqueline Jeruss, an associate professor of surgery and biomedical engineering and a co-author of the study. “Imaging may be done once a patient experiences symptoms, but that implies the number of cancer cells may already be substantial. Improved detection methods are needed to identify metastasis at a point when targeted treatments can have a significant beneficial impact on slowing disease progression.”

The immune cells allowed researchers to identify whether treatments were effective in the mice and which subjects were sensitive or resistant to treatment.

The decoy’s ability to draw immune and cancer cells can also bolster the treatment itself. In previous research, the devices demonstrated an ability to slow the growth of metastatic breast cancer tumors in mice, by reducing the number of cancer cells that can reach those tumors.

In the future, Shea envisions that the scaffolds could be outfitted with sensors and Bluetooth technology that could deliver information in real time without the need for a biopsy.

Learn more: Implantable cancer traps could provide earlier diagnosis, help monitor treatment


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The potential to prevent some spinal cord injuries from resulting in paralysis

Illustration of the human body showing the skeletal system, with the lower spine highlighted in red to indicate pain spots. Image courtesy: Michigan Engineering

An injection of nanoparticles can prevent the body’s immune system from overreacting to trauma, potentially preventing some spinal cord injuries from resulting in paralysis.

The approach was demonstrated in mice at the University of Michigan, with the nanoparticles enhancing healing by reprogramming the aggressive immune cells—call it an “EpiPen” for trauma to the central nervous system, which includes the brain and spinal cord.

“In this work, we demonstrate that instead of overcoming an immune response, we can co-opt the immune response to work for us to promote the therapeutic response,” said Lonnie Shea, the Steven A. Goldstein Collegiate Professor of Biomedical Engineering.

Trauma of any kind kicks the body’s immune response into gear. In a normal injury, immune cells infiltrate the damaged area and clear debris to initiate the regenerative process.

The central nervous system, however, is usually walled off from the rough-and-tumble of immune activity by the blood-brain barrier. A spinal cord injury breaks that barrier, letting in overzealous immune cells that create too much inflammation for the delicate neural tissues. That leads to the rapid death of neurons, damage to the insulating sheaths around nerve fibers that allow them to send signals, and the formation of a scar that blocks the regeneration of the spinal cord’s nerve cells.

All of this contributes to the loss of function below the level of the injury. That spectrum includes everything from paralysis to a loss of sensation for many of the 12,000 new spinal injury patients each year in the United States.

Previous attempts to offset complications from this immune response included injecting steroids like methylprednisolone. That practice has largely been discarded since it comes with side effects that include sepsis, gastrointestinal bleeding and blood clots. The risks outweigh the benefits.

But now, U-M researchers have designed nanoparticles that intercept immune cells on their way to the spinal cord, redirecting them away from the injury. Those that reach the spinal cord have been altered to be more pro-regenerative.

Hopefully, this technology could lead to new therapeutic strategies not only for patients with spinal cord injury but for those with various inflammatory diseases.
Jonghyuck Park

With no drugs attached, the nanoparticles reprogram the immune cells with their physical characteristics: a size similar to cell debris and a negative charge that facilitates binding to immune cells. In theory, their nonpharmaceutical nature avoids unwanted side effects.

With fewer immune cells at the trauma location, there is less inflammation and tissue deterioration. Second, immune cells that do make it to the injury are less inflammatory and more suited to supporting tissues that are trying to grow back together.

“Hopefully, this technology could lead to new therapeutic strategies not only for patients with spinal cord injury but for those with various inflammatory diseases,” said Jonghyuck Park, a U-M research fellow working with Shea.

Previous research has shown success for nanoparticles mitigating trauma caused by the West Nile virus and multiple sclerosis, for example.

“The immune system underlies autoimmune disease, cancer, trauma, regeneration—nearly every major disease,” Shea said. “Tools that can target immune cells and reprogram them to a desired response have numerous opportunities for treating or managing disease.”

Learn more: An ‘EpiPen’ for spinal cord injuries


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Replacing rare earth elements with cheaper more abundant elements

A molecular-beam epitaxy system lays down each atomic layer of the compound in a systematic fashion, so researchers can study the thin layer, or film, structure as they grow it. Image credit: Durbin Lab

Thin-film solar panels, the cell phone in your hand and the LED bulb lighting your home are all made using some of the rarest, most expensive elements found on the planet.

An international team including researchers at the University of Michigan has devised a way to make these kinds of optoelectronic materials from cheaper, more abundant elements. These compounds can also be “tuned” to efficiently harvest electrical energy from the different wavelengths of light in the solar spectrum and to produce the range of colors we like to use in lighting.

Only specific kinds of compounds—a combination of two or more elements—can be used to make electronic devices that efficiently emit light or gather electricity. If you recall in your grade school chemistry classes, each column on the periodic table is considered a group of elements.

For example, group III includes elements such as indium and gallium—both relatively scarce elements that nevertheless currently underpin applications combining light and electricity. The problem is, these compounds often involve elements that are only found in a few locations around the world.

“In fact, we’re in danger of running out of some of those elements because they’re not easy to recycle and they’re in limited supply,” said physicist Roy Clarke, who leads the U-M effort. “It’s not viable for technology to rely on something that’s likely to run out on a scale of 10 to 20 years.”

The research team found a way to combine two common elements from columns bracketing group III to make a novel compound composed of elements from groups II, IV and V. This II-IV-V compound can be used in place of the rare elements typically found in III-V optoelectronic materials with similar properties—except far more abundant and less expensive.

The new compound of zinc, tin and nitrogen can harvest both solar energy and light, so it would work in thin-film solar panels as well as in LED light bulbs, cell phone screens and television displays.

When you’re lighting a home or an office, you want to be able to adjust the warmth of the light, oftentimes mimicking natural sunlight. These new II-IV-V compounds would allow us to do that.

Roy Clarke

Using magnesium instead of zinc further extends the reach of the materials into blue and ultraviolet light. Both compounds are also “tuneable”—that is, when the researchers grow crystals of either compound, the elements can be ordered in such a way that the material is sensitive to specific wavelengths of light.

This tunability is desired because it allows researchers to tweak the material to respond to the widest range of wavelengths of light. This is especially important for light-emitting diodes so that device designers can select the color of light produced.

“When you’re lighting a home or an office, you want to be able to adjust the warmth of the light, oftentimes mimicking natural sunlight,” Clarke said. “These new II-IV-V compounds would allow us to do that.”

Graduate students Robert Makin, Krystal York and James Mathis grew the thin films in the lab of Steve Durbin, a professor of electrical and computer engineering at Western Michigan University.

Makin, who just earned his Ph.D. from WMU and is the lead author of the study, used a technique called molecular beam epitaxy (MBE) to produce the desired compounds under the correct conditions to make films with a carefully controlled degree of atomic ordering.

MBE lays down each atomic layer of the compound in a systematic fashion, so the researchers could study the thin layer, or film, structure as they were growing it. The next phase of the research, leading into construction of various device designs, calls for detailed studies of this material family’s electronic response and testing of various nanoscale architectures which exploit their versatility.

The research team also includes members from the Université de Lorraine in France and the University of Canterbury in New Zealand. Their research is published in Physical Review Letters.

Learn more: How common elements can make a more energy-secure future


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Removal of a single gene can completely block the development of pancreatic cancer – in mice

Dr. Diane Simeone with research fellow Andrea Zamperone in the Simeone Lab.

The action of a gene called ATDC is required for the development of pancreatic cancer, a new study finds.

The work builds on the theory that many cancers arise when adult cells—to resupply cells lost to injury and inflammation—switch back into more “primitive,” high-growth cell types, like those that drive fetal development.

When this reversion happens in the presence of other genetic mistakes, a repair process meant to start and stop quickly continues unchecked.

New details of this cancer-causing switch to primitive cells, and of the role of ATDC in pancreatic cancer formation, are revealed in a study of mice and human patient samples published online May 2 in the journal Genes & Development.

Led by researchers from NYU School of Medicine and the University of Michigan—Ann Arbor, the study found that ATDC must be active if pancreatic cells, when injured, are to reacquire primitive stem-cell qualities and undergo the early steps that lead to the development of pancreatic cancer.

“We found that deleting the ATDC gene in pancreatic cells resulted in one of the most profound blocks of tumor formation ever observed in a well-known mice model engineered to develop pancreatic ductal adenocarcinoma, or PDA, which faithfully mimics the human disease,” says corresponding author Diane Simeone, MD, director of the Pancreatic Cancer Center of NYU Langone Health’s Perlmutter Cancer Center. “We thought the deletion would slow cancer growth, not completely prevent it.”

The search for better treatment in these cases is especially urgent, says Dr. Simeone, given that PDA has the worst prognosis of any major malignancy and is on track to become the second leading cause of cancer-related death by 2030.

Healing Gone Awry

The study focused on acinar cells in the pancreas that secrete digestive enzymes through a network of partnering ducts into the small intestine. These same digestive enzymes can subject this tissue to low levels of damage. In response, acinar cells have evolved to readily switch back into stem cell types that resemble their high-growth ancestors, a feature that they share with pancreatic duct cells.

This ability to regenerate comes at a price, researchers say, because such cells are prone to become cancerous when they also acquire random DNA changes, including those in the gene KRAS that are known to drive aggressive growth in more than 90 percent of pancreatic cancers.

Specifically, stressed acinar cells are known to temporarily undergo acinar-to-ductal metaplasia, or ADM, a step toward a primitive cell type, to resupply cells. This sets the stage for a second shift into pancreatic intraepithelial neoplasia, or PanIN, in which cells no longer multiply under normal controls.

In the current study, the researchers found that mutant KRAS and other genetic abnormalities induced aggressive pancreatic cancer in 100 percent of study mice when the ATDC gene was present and active, but in none of the same cancer-prone mice lacking the gene. Neither did acinar cells in the ATDC “knock-out” mice undergo ADM or transformation to PanIN.

To get a better look at the early steps in pancreatic cancer formation, the research team artificially caused pancreatitis in mice by treating them with cerulein, a signaling protein fragment that damages pancreatic tissue. ATDC gene expression did not increase right after the damage, but did so a few days later and in line with the timeframe required for acinar cells to reprogram genetically into their ductal cell forebears.

Further experiments confirmed that the expression of ATDC triggers beta-catenin, a cell-signaling protein that, upon receiving the right trigger, activates genes including SOX9. Earlier studies linked SOX9 to the development of ductal stem cells and to the aggressive growth seen in PDA. Consistent with this work, the current study found that the inability of cells lacking ATDCto become cancerous was due to their inability to induce SOX9 expression.

The authors also examined ATDC expression in ADM lesions from 12 samples of human pancreatic tissue. The team found it to be more active in human ADM lesions along with beta-catenin and SOX9, and its activation increased further during the transition of ADM into human pancreatic ductal adenocarcinoma.

The findings, says Dr. Simeone, identify ATDC, beta-catenin, SOX9, and their signaling partners as potential targets in the design of new treatment approaches and prevention strategies for pancreatic cancer.

Learn more: Removal of Gene Completely Prevents Development of Aggressive Pancreatic Cancer in Mice


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CRISPR-Cas3: A new type of gene editing CRISPR system is a major advance


A Cornell researcher, who is a leader in developing a new type of gene editing CRISPR system, and colleagues have used the new method for the first time in human cells – a major advance in the field.

The new system, called CRISPR-Cas3, can efficiently erase long stretches of DNA from a targeted site in the human genome, a capability not easily attainable in more traditional CRISPR-Cas9 systems. Though robust applications may be well in the future, the new system has the potential to seek out and erase such ectopic viruses as herpes simplex, Epstein-Barr, and hepatitis B, each of which is a major threat to public health.

“My lab spent the past ten years figuring out how CRISPR-Cas3 works. I am thrilled that my colleagues and I finally demonstrated its genome editing activity in human cells,” said Ailong Ke, professor of molecular biology and genetics and a corresponding author of a paper published April 8 in the journal Molecular Cell. “Our tools can be made to target these viruses very specifically and then erase them very efficiently. In theory, it could provide a cure for these viral diseases.”

The CRISPR-Cas3 technology also allows researchers to scan through the genome and detect non-coding genetic elements, which make up 98 percent of our genome but have not been well characterized. These elements act as regulators that control the expression of proteins in coding genes, and they’ve been found to be pivotal for cell differentiation and sex determination.

CRISPR-Cas3 could be used to efficiently screen for non-coding genetic elements and erase long sequences of DNA. Once erased, researchers may look to see what functions are missing in an organism, to determine the role of that genetic element.

Yan Zhang, assistant professor of biological chemistry at the University of Michigan, is also a corresponding author of the paper. First authors are Adam Dolan, a graduate student in Ke’s lab, and Zhonggang Hou, a research lab specialist in Zhang’s lab.

CRISPR-Cas9 systems use a bacterial RNA as a guide pairs with and recognizes a sequence of DNA. When a match is found, the guide RNA directs CRISPR-associated (Cas) proteins to that precise string of DNA. Once located, the Cas9 protein snips the target DNA at just the right place. CRISPR-Cas3 uses the same mechanism to locate a specific sequence of DNA, however, instead of snipping the DNA in half, its nuclease erases DNA continuously, for up to 100 kilobases.

For the first time, Ke, Zhang and colleagues successfully deleted sequences of up to 100 kilobases of targeted DNA in human embryonic stem cells and in another cell type called HAP1.

While CRISPR-Cas3 holds the potential for a more impactful genome-editing tool than CRISPR-Cas9, the researchers are working to control how long a section they delete. “We can’t quite define the deletion boundaries precisely, and that is a shortcoming when it comes to therapeutics,” Ke said.

Learn more: CRISPR-Cas3 innovation holds promise for disease cures, advancing science


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