The investigation of a simple protein has uncovered its uniquely complicated role in the spread of the childhood cancer, osteosarcoma. It turns out the protein, called ezrin, acts like an air traffic controller, coordinating multiple functions within a cancer cell and allowing it to endure stress conditions encountered during metastasis.

It’s been known that ezrin is a key regulator of osteosarcoma’s spread to the lungs, but its mechanism was not known. Osteosarcoma is a tumour of bone that afflicts children, adolescents and young adults. In most cases, the tumour is localized in the extremities and can be completely removed by surgery or amputation.

“The main cause of death in osteosarcoma patients is not the tumour on their limbs, but the failure of their lungs when the cancer spreads there,” explains Aykut Üren, MD, professor of oncology at Georgetown Lombardi Comprehensive Cancer Center.

Üren and his colleagues have developed molecules that block ezrin’s function and prevent osteosarcoma spread in mouse models. In an attempt to explain the molecular mechanisms underlying ezrin-mediated cancer metastasis, the researchers discovered this previously unrecognized role for ezrin.

“Conventionally ezrin was believed to be functioning only on the inner surface of cancer cells,” Üren says, “but our new discovery indicates that ezrin may operate deeper in the core of the cell and regulate expression of critical genes that are important for cancer’s spread.”

The scientists say that ezrin functions in a new capacity that is unusual for its family of proteins. They found that ezrin’s unusual interaction with another protein called DDX3 results in modulation of genes that give cancer cells an edge in surviving harsh conditions.

“Knowing exactly how ezrin works will help our team develop the ezrin-targeting small molecules as potential new drugs to prevent the spread of cancer cells to lungs in osteosarcoma patients,” Uren says.

“Implications of our findings go beyond cancer research,” says the study’s first author Haydar Çelik, PhD. “Because this work suggests a new molecular mechanism on how ezrin is involved in the regulation of mRNA translation, these observations may provide important clues for scientists investigating how viruses enter and replicate in human cells too.” Georgetown Lombardi Comprehensive Cancer Center

Separating circulating cancer cells from blood cells for diagnostic, prognostic and treatment purposes may become much easier using an acoustic separation method and an inexpensive, disposable chip, according to a team of engineers.

‘Looking for circulating tumour cells in a blood sample is like looking for a needle in a haystack,’ said Tony Jun Huang, professor of engineering science and mechanics.  ‘Typically, the CTCs are about one in every one billion blood cells in the sample.’

Existing methods of separation use tumour-specific antibodies to bind with the cancer cells and isolate them, but require that the appropriate antibodies be known in advance.  Other methods rely on size, deformability or electrical properties.  Unlike conventional separation methods that centrifuge for 10 minutes at 3000 revolutions per minute, surface acoustic waves can separate cells in a much gentler way with a simple, low-cost device.

Acoustic-based separations are potentially important because they are non-invasive and do not alter or damage cells.  However, in order to be effective for clinical use, they also need to be rapidly and easily applicable.

‘In order to significantly increase the throughput for capturing those rare CTCs, device design has to be optimized for much higher flow rates and longer acoustic working length,’ said Ming Dao, principal research scientist, materials science and engineering, Massachusetts Institute of Technology.  ‘With an integrated experimental/modelling approach, the new generation of the device has improved cell sorting throughput more than 20 times higher than previously achieved and made it possible for us to work with patient samples.’

The researchers worked both experimentally and with models to optimize the separation of CTCs from blood.   They used an acoustic-based microfluidic device so that the stream of blood could continuously pass through the device for separation.  Using the differential size and weight of the different cells they chose appropriate acoustic pressures that would push the CTCs out of the fluid stream and into a separate channel for collection.

Tilted-angle standing surface acoustic waves can separate cells using very small amounts of energy. The power intensity and frequency used in this study are similar to those used in ultrasonic imaging, which has proven to be extremely safe, even for fetuses. Also, each cell experiences the acoustic wave for only a fraction of a second.  In addition, cells do not require labelling or surface modification.  All these features make the acoustic separation method, termed acoustic tweezers, extremely biocompatible and maximize the potential of CTCs to maintain their functions and native states.

If two sound sources are placed opposite each other and each emits the same wavelength of sound, there will be a location where the opposing sounds cancel each other. Because sound waves have pressure, they can push very small objects, so a cell or nanoparticle will move with the sound wave until it reaches the location where there is no longer lateral movement, in this case, into the fluid stream that moves the separated cells along.

The researchers used two types of human cancer cells to optimize the acoustic separation — HELA cells and MCF7 cells.  These cells are similar in size.  They then ran an experiment separating these cells and had a separation rate of more than 83 percent.  They then did the separation on other cancer cells, ones for which the device had not been optimized, and again had a separation rate of more than 83 percent.

‘Because these devices are intended for use with human blood, they need to be disposable,’ said Huang.  ‘We are currently figuring out manufacturing and mass production possibilities.’

Physicians could use the devices to monitor how patients reacted to chemotherapy, for initial diagnosis and for determining treatment and prognosis. Penn State University

Psychiatric disorders can be difficult to diagnose because clinicians must rely upon interpreted clues, such as a patient’s behaviours and feelings. For the first time, researchers at University of California, San Diego School of Medicine report identifying a biological marker: the over-production of specific genes that could be a diagnostic indicator of mental illness in female psychiatric patients.

Researchers found that the gene XIST, which is responsible for inactivating one of the two copies of the X chromosome in cells that store genetic material, works overtime in female patients with mental illnesses, such as bipolar disorder, major depression and schizophrenia.
The study suggests that over-production of XIST and genes from the inactive X chromosome are common denominators in the development of psychiatric disorders in patients with rare chromosome disorders, such as Klinefelter syndrome and Triple X syndrome, and in the general population of female psychiatric patients.

“There has been an utmost urgency to identify biomarkers for mental illness that could significantly impact research and drug development,” said Xianjin Zhou, PhD, assistant professor in the Department of Psychiatry at UC San Diego School of Medicine and lead author.

The study was conducted on 60 lymphoblastoid cell lines from female patients, most of whom had a family history of mental illness. Approximately 50 percent of the female patients exhibited abnormally higher levels of XIST and other genes related to the X chromosome.

Zhou and his team said reversing the abnormal activity of the inactive X chromosome in patients suffering from mental illness may offer a potential new strategy for treating psychiatric disorders. UC San Diego

The term intellectual disability covers a large number of clinical entities, some with known cause and others of uncertain origin. For example Down syndrome is due to an extra copy of chromosome 21 and Rett syndrome is in part caused by a mutation in the control switch gene called MeCP2.

In other cases the mechanisms by which they are produced are not clearly identified. It is the case of most of those disorders classified under the large umbrella of autism. An study by Manel Esteller, director of the Program Epigenetics and Cancer Biology (PEBC) of the Bellvitge Biomedical Research Institute (IDIBELL), ICREA researcher and Professor of Genetics at the University of Barcelona , has discovered a mechanism that identifies a cause of intellectual disabilities in these puzzling cases.

‘We have analysed the genome of 215 patients with mental retardation, autism or Rett syndrome, in which they had not found any genetic alteration in the genes classically associated with these clinical conditions, to see if we could find a molecular cause. And this process has allowed us to detect a new mutated gene that could be causing these disorders. ‘He explained Manel Esteller.

‘Specifically, the identified gene is called JMJD1C (Jumonji Domain Containing 1C) and is an epigenetic gene which its normal function is to control the activity of other genes. Only a small percentage of mental retardation of unknown origin is due to mutation of this gene. This finding suggests that many genes with low frequency disturbance are responsible for cases with unknown cause. They have demonstrated that this gene joins the MeCP2 gene so it could also contribute to cases of atypical Rett Syndrome ‘says Esteller. IDIBELL

Cancer DNA circulating in the bloodstream of lung cancer patients can provide doctors with vital mutation information that can help optimise treatment when tumour tissue is not available, an international group of researchers has reported at the European Lung Cancer Conference (ELCC) in Geneva, Switzerland.

The results have important implications for the use of cancer therapies that target specific cancer mutations, explains Dr Martin Reck from the Department of Thoracic Oncology at Lung Clinic Grosshansdorf, Germany, who presented the findings at the conference.

Testing for the presence of these mutations in the tumour itself is not always possible, however studies have suggested that DNA from the tumour that circulates in the bloodstream of patients may provide similar information.

The large international ASSESS study aimed to compare the ability of blood testing to detect EGFR mutations with the more standard method of testing the tumour itself.

“We were really asking a question on behalf of patients,” Reck said: “Is there a valid test that can identify an EGFR mutation and give me the opportunity for superior treatment, even if my lung tumour is not accessible for bronchoscopy or CT-guided biopsy? And, are the results of this blood test in agreement with the results of the ‘gold-standard’ tissue test?”

Overall, the study included 1162 matched tissue and blood samples. Comparison of the outcomes of EGFR testing in the two techniques showed an 89% rate of agreement between the blood test and tissue test. Plasma testing identified about half of the patients with EGFR mutations, compared to tissue testing (a sensitivity of 46%).

The tests in this study were not performed in specially selected central labs, but in local labs that are used for daily clinical routine. “This is important, because it does reflect the clinical reality and not a ‘virtual’ trial reality,” Reck said.

“The results mean that for patients who do not have accessible tumour tissue, plasma testing for EGFR mutation turns out to be an attractive option to offer these patients adequate targeted treatment,” Reck added.

Commenting on the study, Dr Rafael Rosell, from the Catalan Institute of Oncology, Barcelona, Spain, expert on the ESMO Faculty on Lung cancer, said: “Cell-free DNA detected in the bloodstream of cancer patients represents an excellent tool to examine genetic alterations that are usually  found through tumour tissue testing. This represents one of the most astonishing phenomena in biology.”

“The results of this study validate that the presence of EGFR mutations in circulating DNA from plasma or serum (fractions obtained from whole blood) can be detected in around half of the patients.”

Already, since this study was performed, improvement of techniques have seen the sensitivity of tests for EGFR mutations in circulating tumour DNA increase further, Rosell noted.

“This work paves the way for further studies and expands the routine use of examining mutations such as EGFR mutations as part of cancer patient care,” Rosell said. European Society for Medical Oncology