A team led by scientists at The Scripps Research Institute (TSRI) and Johns Hopkins University School of Medicine has uncovered a big clue to how bacteria may promote some colon cancers.

The study used novel metabolomic technologies to reveal molecular evidence suggesting a vicious circle in which cancerous changes in colon cells promote the growth of bacterial conglomerations called biofilms, and biofilms in turn promote cancer development.

On the whole, the findings suggest that removing bacterial biofilms could be a key strategy for preventing and treating colon cancers, which currently kill about 50,000 Americans per year. The study also revealed an apparent metabolic marker of biofilm-associated colon cancers.

The research, which used sophisticated “metabolomics” techniques, was a collaboration between groups led by Gary Siuzdak, professor of chemistry, molecular and computational biology and senior director of the Scripps Center for Metabolomics at TSRI, Cynthia L. Sears, professor of medicine, oncology and molecular microbiology and immunology at the Johns Hopkins University School of Medicine and Bloomberg School of Public Health, and David Edler, associate professor at the Karolinska Institute.

A previous study led by Sears and colleagues provided evidence that the tissue in and around cancers of the ascending colon, on the right side of the abdomen, almost always harbours bacterial conglomerations called biofilms.

“In the current study, we wanted to understand more about what was happening,” said Caroline H. Johnson, member of the Scripps Center for Metabolomics and co-first author of the new report with Christine M. Dejea of Johns Hopkins. “In particular, we wanted to determine if there was a metabolic link between the biofilm and colon cancer.”

Metabolites are small molecules in blood and tissues that are products of the myriad metabolic processes in cells. More than 10,000 distinct metabolites normally can be found in humans.

The team began the search with an “unbiased screen,” a wide-net technique—using advanced liquid chromatography and mass spectrometry and their XCMS metabolomic cloud-based platform—that registered the levels of thousands of metabolites in a set of colon tissue samples from patients at Johns Hopkins and at the Karolinska Institute in Sweden.

The data showed that polyamines were important in general and one metabolite—N1, N12-diacetylspermine—was particularly prominent, on average about nine times more abundant in cancerous tissue, compared to nearby non-cancerous tissue.

In further tests, the team found that even among cancerous samples, the same metabolite was four times more abundant in the presence of biofilms. In other words, the cancerous cells and the biofilms both seemed to be contributing to its overproduction.

With a sophisticated technique called “nanostructure imaging mass spectrometry” (NIMS), the team was able to map the precise locations of N1, N12-diacetylspermine in tissue samples, confirming its higher levels in both tumours and biofilms.

The researchers also carried out a technique called “global isotope metabolomics,” using an isotope of N1, N12-diacetylspermine to trace its metabolic fate in cells in an unbiased manner, finding that it appears to be a metabolic end-product.

That colon tumours would produce abnormally high amounts of N1, N12-diacetylspermine is not surprising. The molecule belongs to a family of metabolites called polyamines, which are known to have roles in driving cell growth and which are commonly up-regulated in cancers as well as in healthy fast-growing tissues. N1, N12-diacetylspermine itself has been observed at higher levels in colon cancer and is considered a potential biomarker for early cancer diagnosis.

But why would bacterial biofilms also be linked to higher levels of N1, N12-diacetylspermine? It turns out that bacteria, too, use polyamines to drive their own cells’ proliferation and to build biofilms. Polyamines are such ancient, ubiquitous molecules that bacteria apparently can even use those produced by their animal hosts.

Thus, biofilms may promote cancer in the colon by inducing chronic inflammation and associated cell proliferation. That increased cell proliferation would be accompanied by a rise in the production of polyamines. Resident bacteria, in turn, could use this abundance of polyamines to make more biofilms—completing the vicious circle. Along the way, levels of the by-product N1, N12-diacetylspermine would be driven higher and higher. The Scripps Research Institute

A team of scientists, part of the international effort to curb further spread of the Ebola virus in Sierra Leone, has released its first dataset of the virus’ genetic structure online. The dataset will allow the global scientific community to monitor the pathogen’s evolution in real-time and conduct research that can lead to more effective strategies against further outbreaks.

The team of British scientists, funded by the Wellcome Trust, is using semi-conductor next-generation sequencing technology developed by Thermo Fisher Scientific to generate data in a lab facilitated by Public Health England and International Medical Corps. The genetic analysis is being made freely available to the scientific community.

Since the first reported case in March 2014, the Ebola outbreak has claimed nearly 11,000 lives in West African countries. Professor Ian Goodfellow, Head of Virology at the University of Cambridge, travelled to Sierra Leone in December last year and then again in March this year to help set up a new diagnostics centre attached to an Ebola Treatment Centre in one of the country’s worst affected parts. He returned a third time, together with his postdoc Dr Armando Arias, to study the virus at a molecular level using the sequencing technology.

“Sequencing the genome of a virus can tell us a lot about how it spreads and changes as it passes from person to person. While this information is invaluable to researchers, the rapid sharing of data does not always occur,” said Professor Paul Kellam at the Wellcome Trust Sanger Institute, who is leading the team to map the genomic data captured by Professof Goodfellow and colleagues. “It used to take months to process samples that had to be brought back to labs in the UK for analysis. Having sequencing capabilities on the ground helps generate data in a matter of days or at the longest weeks, which should have a profound impact on how the Ebola virus is researched and inevitably addressed on a global scale.”

Rapid sequencing enables epidemiologists to decipher the source of individual strains, and helps eliminate the need to rely upon Ebola patients to tell them how and where they contracted the virus, as different strains can be tracked as they are transmitted from person to person.

“Only by understanding the Ebola virus and other pathogens, which cause so much suffering in countries like Sierra Leone, can we take meaningful steps to protect communities from future outbreaks,” said Goodfellow. “My hope is that this technology will be used by the next generation of Sierra Leonean scientists and researchers to help provide a sustainable research and surveillance system in the future.” University of Cambridge

​Cancer’s ability to grow unchecked is often attributed to cancer stem cells, a small fraction of cancer cells that have the capacity to grow and multiply indefinitely. How cancer stem cells retain this property while the bulk of a tumour’s cells do not remains largely unknown. Using human tumour samples and mouse models, researchers at University of California, San Diego School of Medicine and Moores Cancer Center discovered that cancer stem cell properties are determined by epigenetic changes — chemical modifications cells use to control which genes are turned on or off.
The study reports that an enzyme known as Lysine-Specific Demethylase 1 (LSD1) turns off genes required to maintain cancer stem cell properties in glioblastoma, a highly aggressive form of brain cancer. This epigenetic activity helps explain how glioblastoma can resist treatment. What’s more, drugs that modify LSD1 levels could provide a new approach to treating glioblastoma.

The researchers first noticed that genetically identical glioblastoma cells isolated from patients differed in their tumourigenicity, or capacity to form tumours, when transplanted to mouse models. This observation suggested that epigenetics, rather than genetics (DNA sequence), determines tumourigenicity in glioblastoma cancer stem cells.

“One of the most striking findings in our study is that there are dynamic and reversible transitions between tumorigenic and non-tumorigenic states in glioblastoma that are determined by epigenetic regulation,” said senior author Clark Chen, MD, PhD, associate professor of neurosurgery and vice-chair of research and academic development at UC San Diego School of Medicine.
Probing further, Chen’s team discovered that the epigenetic factor determining whether or not glioblastoma cells can proliferate indefinitely as cancer stem cells is their relative abundance of LSD1. LSD1 removes chemical tags known as methyl groups from DNA, turning off a number of genes required for maintaining cancer stem cell properties, including MYC, SOX2, OLIG2 and POU3F2.

“This plasticity represents a mechanism by which glioblastoma develops resistance to therapy,” Chen said. “For instance, glioblastomas can escape the killing effects of a drug targeting MYC by simply shutting it off epigenetically and turning it on after the drug is no longer present. Ultimately, strategies addressing this dynamic interplay will be needed for effective glioblastoma therapy.”
Chen and one of the study’s first authors, Jie Li, PhD, note that the epigenetic changes driving glioblastoma are similar to those that take place during normal human development.
“Though most cells in our bodies contain identical DNA sequences, epigenetic changes help make a liver cell different from a brain cell,” said Li, an assistant project scientist in Chen’s lab. “Our results indicate that the same programming processes determine whether a cancer cell can grow indefinitely or not.” University of California – San Diego Health

Massachusetts General Hospital (MGH) investigators have identified an inflammatory molecule that appears to play an essential role in the autoimmune disorder systemic lupus erythematosus, commonly known as lupus.  In their report, the researchers describe finding that a protein that regulates certain cells in the innate immune system – the body’s first line of defence against infection – activates a molecular pathway known to be associated with lupus and that the protein’s activity is required for the development of lupus symptoms in a mouse model of the disease.

“This study is the first demonstration that the receptor TREML4 amplifies the cellular responses transmitted through the TLR7 receptor and that a lack of such amplification prevents the inflammatory overactivation underlying lupus,” says Terry Means, PhD, of the Center for Immunology and Inflammatory Diseases in the MGH Division of Rheumatology, Allergy, and Immunology.  “Our preliminary results suggest that TREML4-regulated signalling through TLR7 may be a potential drug target to limit inflammation and the development of autoimmunity.”

Lupus is an autoimmune disorder characterized by periodic inflammation of joints, connective tissues and organs including heart, lungs, kidneys and brain.  TLR7 is one of a family of receptors present on innate immune cells like macrophages that have been linked to chronic inflammation and autoimmunity.   Animal studies have suggested that overactivation of TLR7 plays a role in lupus, and a gene variant that increases expression of the receptor has been associated with increased lupus risk in human patients.  The current study was designed to identify genes for other molecules required for TLR7-mediated immune cell activation.

The MGH-based team conducted an RNA-interference-based genome-scale screen of mouse macrophages, selectively knocking down the expression of around 8,000 genes, and found that TREML4 – one of a family of receptors found on granulocytes and monocytes – amplifies the response of innate immune cells to activation via TLR7.  Immune cells from mice lacking TREML4 showed a weakened response to TLR7 activation. When a strain of mice genetically destined to develop a form of TLR7-dependent lupus was crossbred with a strain in which TREML4 expression was suppressed, offspring lacking TREML4 were protected from the development of lupus-associated kidney failure and had significantly lower blood levels of inflammatory factors and autoantibodies than did mice expressing TREML4. 

Means notes that identifying the potential role of TREML4 in human lupus may lead to the development of drugs that could prevent or reduce the development or progression of lupus and another autoimmune disorder called Sjögren’s syndrome, which also appears to involve TLR7 overactivation.  Future studies are needed to better define the molecular mechanism behind TREML4-induced amplification of TLR7 signaling and to clarify beneficial reactions controlled by TREML4 – for example, the immune response to influenza virus, which the current study found was inhibited by TREML4 deficiency. Massachusetts General Hospital