The discovery of a gene mutation that causes a rare premature aging disease could lead to the development of drugs that block the rapid, unstoppable cell division that makes cancer so deadly.

Scientists at the University of Michigan and the U-M Health System recently discovered a protein mutation that causes the devastating disease dyskeratosis congenita, in which precious hematopoietic stem cells can’t regenerate and make new blood. People with DC age prematurely and are prone to cancer and bone marrow failure.

But the study findings reach far beyond the roughly one in 1 million known DC patients, and could ultimately lead to developing new drugs that prevent cancer from spreading, said Jayakrishnan Nandakumar, assistant professor in the U-M Department of Molecular, Cellular, and Developmental Biology.

The DC-causing mutation occurs in a protein called TPP1. The mutation inhibits TPP1’s ability to bind the enzyme telomerase to the ends of chromosomes, which ultimately results in reduced hematopoietic stem cell division. While telomerase is under-produced in DC patients, the opposite is true for cells in cancer patients.

‘Telomerase overproduction in cancer cells helps them divide uncontrollably, which is a hallmark of all cancers,’ Nandakumar said. ‘Inhibiting telomerase will be an effective way to kill cancer cells.’

The findings could lead to the development of gene therapies to repair the mutation and start cell division in DC patients, or drugs to inhibit telomerase and cell division in cancer patients. Both would amount to huge treatment breakthroughs for DC and cancer patients, Nandakumar said.

Nandakumar said that a major step moving forward is to culture DC patient-derived cells and try to repair the TPP1 mutation to see if telomerase function can be restored. Ultimately, the U-M scientist hopes that fixing the TPP1 mutation repairs telomerase function and fuels cell division in the stem cells of DC patients.

‘It’s conceivable that with the recent advancement in human genome-editing technology, we could, in the not-so-distant future, repair the mutation in hematopoietic stem cells in the bone marrow of DC patients,’ Nandakumar said.

The findings also reinforce how one tiny change in an amino acid chain can cause devastating health consequences.

‘It was surprising to us that just deleting one single amino acid in a protein chain that is 544 amino acids long can result in such a severe disease,’ Nandakumar said. University of Michigan

Researchers at UT Southwestern Medical Center have found an “Achilles heel” in a metabolic pathway crucial to stopping the growth of lung cancer cells.

At the heart of this pathway lies PPARγ (peroxisome proliferation-activated receptor gamma), a protein that regulates glucose and lipid metabolism in normal cells. Researchers demonstrated that by activating PPARγ with antidiabetic drugs in lung cancer cells, they could stop these tumour cells from dividing.

“We found that activation of PPARγ causes a major metabolic change in cancer cells that impairs their ability to handle oxidative stress,” said Dr. Ralf Kittler, Assistant Professor in the Eugene McDermott Center for Human Growth and Development, the Department of Pharmacology, the Harold C. Simmons Cancer Center, and the Cecil H. and Ida Green Center for Reproductive Biology Sciences at UT Southwestern.

“The increased oxidative stress ultimately inhibits the growth of the tumour. We found that activation of PPARγ killed both cancer cells grown in a dish and tumours in mice, in which we observed near complete tumour growth inhibition,” said Dr. Kittler, the John L. Roach Scholar in Biomedical Research of UT Southwestern’s Endowed Scholars Program.

The study builds on a large body of work showing that metabolism in cancer cells is altered when compared to normal cells. Changes in metabolism can make cancer cells more vulnerable to therapeutic agents, which make them a good target to investigate for cancer therapy.  The new research also extends earlier observations made by Dr. Steven Kliewer, Professor of Molecular Biology and Pharmacology, who first identified that thiazolidinediones target PPARγ. Dr. Kliewer holds the Nancy B. and Jake L. Hamon Distinguished Chair in Basic Cancer Research.

Dr. Kittler and his team determined that PPARγ activation triggers changes in glucose and lipid metabolism that cause an increase in the levels of reactive oxygen species (ROS). ROS are highly reactive oxygen-containing molecules that damage cells when present at high levels, a phenomenon known as oxidative stress. It is this increase in ROS that eventually stops the cancer cells from dividing.

“The abnormal metabolism in cancer cells frequently causes increased oxidative stress, and any further increase can ‘push’ cancer cells over  the cliff,” said Dr. Kittler, UT Southwestern’s first Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research.

The findings suggest that targeting PPARγ could be a promising new therapeutic approach for lung cancer and potentially other cancers. The researchers saw that activating PPARγ caused similar molecular changes in breast cancer cells.

“This is an important finding because the drugs that activate PPARγ include FDA-approved antidiabetic drugs that are relatively well tolerated compared to chemotherapy. Knowing their mechanism of action provides us with clues for selecting tumours that may be responsive to this treatment, for combining these drugs with anti-cancer drugs to make therapy more effective, and for developing markers to measure the response of tumours to these drugs in patients,” said Dr. Kittler, Director of the McDermott Next-Generation Sequencing Core at UT Southwestern.

“Of course, further study will be required to determine the therapeutic effectiveness of PPARγ-activating drugs for lung cancer treatment,” he added. UT Southwestern Medical Center

Scientists have been labouring to detect cancer and a host of other diseases in people using promising new biomarkers called “exosomes.” Indeed, Popular Science magazine named exosome-based cancer diagnostics one of the 20 breakthroughs that will shape the world this year. Exosomes could lead to less invasive, earlier detection of cancer, and sharply boost patients’ odds of survival.

“Exosomes are minuscule membrane vesicles — or sacs — released from most, if not all, cell types, including cancer cells,” said Yong Zeng, assistant professor of chemistry at the University of Kansas. “First described in the mid-’80s, they were once thought to be ‘cell dust,’ or trash bags containing unwanted cellular contents. However, in the past decade scientists realized that exosomes play important roles in many biological functions through capsuling and delivering molecular messages in the form of nucleic acids and proteins from the donor cells to affect the functions of nearby or distant cells. In other words, this forms a crucial pathway in which cells talk to others.”

While the average piece of paper is about 100,000 nanometers thick, exosomes run just 30 to 150 nanometers in size. Because of this, exosomes are hard to separate out and test, requiring multiple-step ultracentrifugation — a tedious and inefficient process requires long stretches in the lab, according to scientists.

“There aren’t many technologies out there that are suitable for efficient isolation and sensitive molecular profiling of exosomes,” said Zeng.  “First, current exosome isolation protocols are time-consuming and difficult to standardize. Second, conventional downstream analyses on collected exosomes are slow and require large samples, which is a key setback in clinical development of exosomal biomarkers.”

Now, Zeng and colleagues from the University of Kansas Medical Center and KU Cancer Center have just published a breakthrough paper in the Royal Society of Chemistry journal describing their invention of a miniaturized biomedical testing device for exosomes. Dubbed the “lab-on-a-chip,” the device promises faster result times, reduced costs, minimal sample demands and better sensitivity of analysis when compared with the conventional bench-top instruments now used to examine the tiny biomarkers.

“A lab-on-a-chip shrinks the pipettes, test tubes and analysis instruments of a modern chemistry lab onto a microchip-sized wafer,” Zeng said. “Also referred to as ‘microfluidics’ technology, it was inspired by revolutionary semiconductor electronics and has been under intensive development since the 1990s. Essentially, it allows precise manipulation of minuscule fluid volumes down to one trillionth of a litre or less to carry out multiple laboratory functions, such as sample purification, running of chemical and biological reactions, and analytical measurement.”

Zeng and his fellow researchers have developed the lab-on-a-chip for early detection of lung cancer — the number-one cancer killer in the U.S. Today, lung cancer is detected mostly with an invasive biopsy, after tumours are larger than 3 centimetres in diameter and even metastatic, according to the KU researcher.

Using the lab-on-a-chip, lung cancer could be detected much earlier, using only a small drop of a patient’s blood.

“Most lung cancers are first diagnosed based on symptoms, which indicate that the normal lung functions have been already damaged,” Zeng said. “Unlike some cancer types such as breast or colon cancer, no widely accepted screening tool has been available for detecting early-stage lung cancers. Diagnosis of lung cancer requires removing a piece of tissue from the lung for molecular examination. Tumour biopsy is often impossible for early cancer diagnosis as the developing tumour is too small to see by the current imaging tools. In contrast, our blood-based test is minimally invasive, inexpensive, and more sensitive, thus suitable for large population screening to detect early-stage tumours.”

Zeng said the prototype lab-on-a-chip is made of a widely used silicone rubber called polydimethylsiloxane and uses a technique called “on-chip immunoisolation.”

“We used magnetic beads of 3 micrometres in diameter to pull down the exosomes in plasma samples,” Zeng said. “In order to avoid other interfering species present in plasma, the bead surface was chemically modified with an antibody that recognizes and binds with a specific target protein — for example, a protein receptor — present on the exosome membrane. The plasma containing magnetic beads then flows through the microchannels on the diagnostic chip in which the beads can be readily collected using a magnet to extract circulating exosomes from the plasma.”

Beyond lung cancer, Zeng said the lab-on-a-chip could be used to detect a range of potentially deadly forms of cancer.

“Our technique provides a general platform to detecting tumour-derived exosomes for cancer diagnosis,” he said. “In addition to lung cancer, we’ve also tested for ovarian cancer in this work. In theory, it should be applicable to other types of cancer. Our long-term goal is to translate this technology into clinical investigation of the pathological implication of exosomes in tumour development. University of Kansas

An international team of researchers led by KU Leuven has developed a new test to help doctors diagnose ovarian tumours and choose the most appropriate treatment. The researchers have recently described the test called ADNEX `

Existing predication models for ovarian cancer discriminate between benign and malignant tumours but lack accuracy and are unable to sub-classify different types of malignant tumour. This makes determining the appropriate treatment difficult, since some ovarian tumours require more serious treatment than others.

The new test developed by Professor Ben Van Calster (KU Leuven) in cooperation with the International Ovarian Tumour Analysis group (IOTA) not only discriminates between benign and malignant tumours but also makes it possible to accurately identify and classify malignant tumours into four types: borderline, stage 1 invasive, stage II-IV invasive and secondary metastatic.

The test is based on the patient’s clinical information, a simple tumour marker blood test and features that can be identified on an ultrasound scan. In addition to identifying the type of tumour, the test also expresses the confidence of the diagnosis as a percentage.

Doctors can use the test in a clinical database or by entering the patient’s details into a smartphone app, which was demonstrated to gynaecologists at the International Society for Ultrasound in Obstetrics and Gynecology World Congress in Barcelona last month. The authors of the study say doctors could start using ADNEX straight away.

Successful treatment depends in large part on the correct identification of the type of tumour, but this can be difficult. As a result, many women with ovarian cancer are not referred to the right specialist and some undergo more serious operations than necessary. A benign ovarian tumour often does not even need treatment at all.

But for malignant tumours especially, determining the tumour type is crucial to selecting the right specialist surgeon and treatment.

The researchers developed the test using data from almost 6,000 ovarian cancer patients, which were gathered and analysed by the IOTA group led by Professor Dirk Timmerman of UZ Leuven (University Hospitals Leuven), KU Leuven’s network of research hospitals. University of Leuven

University of Utah scientists have identified two microRNA molecules that control chronic inflammation, a discovery that one day may help researchers prevent certain fatal or debilitating conditions before they start.

‘We’re living at a time where the aging population is growing,’ said Ryan O’Connell, D.Phil., assistant professor of pathology, whose lab made the discovery. ‘The question is: how can we predict and prevent the onset of disorders that emerge upon growing older?’

After three years of research and building on previous studies, the scientists determined that if a particular microRNA is genetically removed from mice, the animals will develop chronic inflammation spontaneously and die early from subsequent ailments such as cancer or an autoimmune disorder. However, mice that also lack a second type of microRNA don’t develop chronic inflammation. So one microRNA prevents the condition while the other promotes it, identifying a key system in the body that modulates this harmful state.

Certain types of immune cells, called T follicular helper cells, are known to promote the production of antibodies that attack our own tissues and contribute to chronic inflammation. O’Connell and colleagues found that the microRNAs at issue are produced by and act to control these important cell types.

‘Now we know which cells in the body we need to get miRNA inhibitors delivered to if we want to reduce chronic inflammatory conditions,’ said O’Connell, noting that the next step is human research. One question would be whether patients with chronic inflammation who received an inhibitor of a certain microRNA would see their chronic inflammation indicators decrease, preventing fatal conditions from emerging.

Previous studies have shown that chronic inflammation is linked to the development of certain conditions including diabetes, lupus, arthritis, obesity, cancer, neurodegeneration and cardiovascular disease along with a shortened life span. The challenge is that chronic inflammation happens at a low level and is typically not detected by doctors. But certain biomarkers such as elevated levels of cytokines or antibodies can indicate the condition.

‘Everyone waits until they have bad symptoms to go see the doctor,’ he said. ‘However, the goal of medicine is to take a person who is not sick yet and be able to analyze something we can test that can help predict whether they’re going to be sick in the future — and take appropriate measures to prevent terrible outcomes.’ EurekAlert