A study by researchers at IRB Barcelona explains the basis for the classification of colon tumours in good or bad prognosis by analysing the tissue surrounding the tumour cells.

The scientists are currently developing a test that enables the identification of patients at risk of relapse after surgical removal of the tumour by measuring 4-6 genes expressed by the tumour microenvironment.

The researchers also propose to test in patients a particular drug that blocks the metastatic capacity of colorectal cancers in mice.

This drug has been tested using novel technology that allows the growth of mini colon cancers, also known as organoids, derived from patient samples.
About 40–50% of all colorectal patients relapse in the form of metastasis. In the last three years, several molecular classifications have been proposed to identify colorectal cancer patients at risk of relapse. Scientists headed by ICREA researcher Eduard Batlle at the Institute for Research in Biomedicine (IRB Barcelona) explain why these classifications work and reveal, in fact, that they can be simplified and improved by looking exclusively at the genes that are expressed in the tissue around the tumour, known as the stroma or tumour microenvironment.

“We have re-evaluated the classifications under our perspective and confirmed that colon cancer relapse occurs in patients in which tumour cells have the capacity to disrupt the tissue surrounding the tumour,” explains Eduard Batlle, head of the Colorectal Cancer Laboratory at IRB Barcelona. The team of scientists have examined the genetic profile of around 1,000 tumours from patients all over the world. “The conclusion is indisputable. The key to the classifications lies in whether the stroma of the tumour is altered or not and it is this property that confers malignancy to colon tumours. Patients with unaltered stroma are essentially cured after surgery.”

This new approach to addressing different types of colon tumour will soon have a practical application for doctors. On one hand, the scientists demonstrate that tumour cells communicate with the stroma through the hormone TGF-beta and that metastasis could be prevented in these patients by interfering with this communication. “We propose exploring the possibility of using TGF-beta inhibitors to treat colon cancer”. Several TGF-beta inhibitors are being tested for other kinds of tumours. “The data are impressive. It would be most pertinent for oncologists and pharmaceutical companies to come to an agreement in order to start clinical assays in patients with poor prognosis colon cancer” says Alexandre Calon, postdoctoral researcher and first author of the article. To test the use of these inhibitors, the scientists at IRB Barcelona have developed technology that allows them to grow mini colon tumours in vitro, also known as organoids, from samples taken from patients. “These organoids reproduce the behaviour of the original tumour and are therefore a powerful tool for personalised cancer treatment,” explains Batlle. 

Furthermore, the IRB Barcelona researchers are very close to achieving a diagnostic test named Colostage to identify those patients at the greatest risk of a relapse in the form of metastasis. “By focusing on the genetic programme of the tissue surrounding the tumour we can identify the vast majority of patients that will experience relapse. This would allow better discrimination of which patients to treat and follow up, as the use of radiotherapy or chemotherapy would benefit only this group” ensures the researcher. In addition, this test will help identify those patients more likely to benefit from the use of TGF-beta inhibitors in clinical trials. IRB Barcelona

A new study led by researchers at King’s College London in collaboration with the University of Manchester and the University of Dundee has found a strong link between exposure to peanut protein in household dust during infancy and the development of peanut allergy in children genetically predisposed to a skin barrier defect.

Around 2% of school children in the UK and the US are allergic to peanuts. Severe eczema in early infancy has been linked to food allergies, particularly peanut allergy. A major break-through in the understanding of eczema developed with the discovery of the FLG gene which codes for the skin barrier protein filaggrin. Mutations in the FLG gene result in an impaired skin barrier which is thought to allow allergens to penetrate the skin and predispose the body towards an allergic response.

Immunology, looked at the amount of peanut protein children were exposed to in household dust in their first year of life by vacuuming dust from the living room sofa and measuring peanut in the dust. A group of 577 children were assessed at 8 and 11 years of age for peanut allergy and their DNA was checked for FLG mutations. The study was conducted in children recruited to the Manchester Asthma and Allergy Study.

A strong link was found between early-life exposure to peanut protein in household dust and peanut allergy in children with FLG mutations. A three-fold increase in house dust peanut exposure during infancy was associated with a three-fold increase in risk of school-age peanut allergy. One in five children with peanut allergy had an FLG mutation. There was no significant effect of environmental peanut exposure in children without FLG mutations.

Dr Helen A Brough, first author from the Department of Paediatric Allergy, Division of Asthma, Allergy & Lung Biology, King’s College London, said: “Our findings provide evidence that peanut allergy may develop via the skin in children with mutations in the gene that codes for filaggrin which damage the function of this important skin protein. These findings are also an example of how an individual’s response to their environment can be modified by their genes. Our study raises the possibility of being able to identify a group of children with FLG mutations through genetic testing in the future, and altering their environmental exposure to peanut early in life to reduce the risk of developing peanut allergy.” King’s College London

A team led by Ludwig and Memorial Sloan Kettering (MSK) researchers has published a landmark study on the genetic basis of response to a powerful cancer therapy known as immune checkpoint blockade. Their paper describes the precise genetic signatures in melanoma tumours that determine whether a patient will respond to one such therapy. It also explains in exquisite detail how those genetic profiles translate into subtle molecular changes that enable the immune system attack of cancer cells in response to immune checkpoint blockade.

“The genetic signature we have found will be invaluable to understanding the biological mechanisms that drive therapeutic responses to immunotherapy for metastatic melanoma,” says Jedd Wolchok, MD, PhD, director of the Ludwig Collaborative Laboratory and associate director of the Ludwig Center for Cancer Immunotherapy at MSK, who co-led the study with Timothy Chan, MD, PhD, of MSK’s Human Oncology and Pathogenesis Program. “Further, our strategy can now be applied to determine the genetic signatures associated with the efficacy of a number of other immunotherapies and cancers.”

Few approaches to treating cancer have generated as much excitement as immunotherapy, in which the immune system is engaged to destroy malignancies. One class of such treatments targets CTLA-4, a molecule expressed on the surface of killer T cells that ordinarily blocks their proliferation. Antibody drugs that block CTLA-4 thus stimulate killer T cell responses—which can target cancer cells—and significantly extend survival for many melanoma patients. Yet not all patients respond equally to this treatment: some, remarkably, survive many years; others fail to respond at all.

“There is a subset of melanoma patients who are living far longer than anyone would have expected in the past, largely because of this treatment and other recently developed targeted and immunologic treatments,” says Wolchok. “But we did not know how to identify them, and that’s what really drove this investigation.”

Cancer cells are swift but sloppy proliferators, generating countless mutations across their genome as they multiply. Those mutations are often expressed as changes in the chains of amino acids that make protein molecules. Like all cells, cancer cells chop up and hold out short fragments of such proteins—each about 9 amino acids in length—for the immune system to assess. These “peptides” are held up and presented to immune cells by a protein complex known as MHC Class I, which varies significantly between people.

“Previous studies by Jedd and others had shown that the particular MHC type of a patient doesn’t appear to influence the efficacy of CTLA-4 blockade,” says Chan. “So we decided to see if the tumour genome has anything to say about whether or not people respond to this therapy. The result was entirely unexpected, and the answer is exceedingly important.”

Chan, Wolchok and their colleagues initially hypothesized that tumours that harboured highly mutated cells would be most responsive to CTLA-4 blockade. To test that hypothesis, they sequenced and compared all of the genes expressed as proteins (collectively known as the “exome”) in tumours taken from 25 patients treated with anti-CTLA-4 antibodies and found that this was, to some degree, true. “But looking at the data a little more deeply,” says Wolchok, “we saw that there were outliers—patients who had over one thousand mutations who didn’t respond, and some with just a few dozen who did. This was a strong indication that the quality of the mutations matters.”

A sophisticated computational analysis of the cancer genomes revealed that a set of core peptide sequences—each four amino acids long (tetrapeptides)—within MHC Class I-presented peptides were unequivocally associated with response to treatment. To test the prognostic power of this genetic signature, the researchers sequenced the exomes of tumours from another 39 melanoma patients treated with CTLA-4 blockade. They found that all those in this set who had responded to the therapy had at least one and typically several more of the tetrapeptides they had identified. Those who failed to respond did not. Their results show that the mutant DNA sequences, can occur anywhere in the genome—not just within mutant “driver” genes that are already known to contribute to cancer.

“The more mutated the tumor’s genome is,” says Chan, “the more likely it is that immunotherapy will work. Since tumours induced by tobacco—such as those of non-small cell lung cancer—have more mutations than most other cancers except melanoma, this finding has enormous medical implications for these genetically diverse cancers.”

It also helps explain, says Wolchok, why the relatively more mutated cancers have been found in clinical trials to be the most responsive to checkpoint blockade. Ludwig Cancer Research

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Scientists from UCL and Queen Mary University of London have identified what they believe could be a cause of pre-term premature rupture of the foetal membrane (PPROM) which accounts for 40 per cent of pre-term births, the main reason for infant death world-wide.

The researchers used bioengineering techniques to test the effect of repetitive stretch on tissues of the amniotic membrane which surrounds and protects the baby prior to birth.

They found that stretching of the amniotic membrane leads to the overproduction of prostaglandin E2 (PGE2) which is damaging to both the cells and mechanical structure of the tissue. This overproduction activates the stretch-sensitive protein connexin 43 (Cx43) and reduces the mechanical properties of the membrane potentially, leading to rupture and pre-term birth.

The research is the first to look at the role of Cx43 in causing PPROM.

The team are now researching possible treatments that would allow the amniotic membrane to be repaired.

Co-author of the research, Dr Tina Chowdhury from the School of Engineering and Material Sciences at Queen Mary University of London, said, “To have potentially found a way to reduce pre-term births and prevent early deaths of young babies worldwide is incredibly exciting. The unique bioengineering tools at QMUL have allowed us to test the tissue in a way that has never been done before. This gives us an understanding of both the mechanical as well as biological mechanisms involved and will help us to develop therapies that will reduce the number of pre-term births.”

Dr Anna David, a consultant in obstetrics and pre-term birth from the UCL Institute for Women’s Health and a co-author of the paper, said,“Our findings have provided a new understanding of why pregnant women who have pre-term contractions go on to rupture their membranes early. The new project funded by the Rosetrees Trust could lead to a therapy that will heal the amniotic membrane and reduce preterm births. This has the potential to save many lives worldwide and improve the health and well-being of women during pregnancy and their families after birth.” University College London