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Precision cancer medicine requires personalized biomarkers to identify patients who will benefit from specific cancer therapies. In an effort to improve the accuracy of predictions about prognosis for patients with breast cancer and the efficacy of personalized therapy, University of North Carolina Lineberger Comprehensive Cancer Center researchers have developed a method to precisely identify individual patients who have aggressive breast cancer. The new approach involves sorting and characterizing invasive breast cancer cells by epigenetic characteristics – a method that involves analysing how particular regulatory proteins interact with DNA to control their expression – as well as by how the genes are amplified or abnormally expressed. The researchers reported that they used this technique to identify potential new prognostic markers to predict distinct clinical outcomes for two major subtypes of breast cancer.

“This paper describes a ground-breaking multi-omics technology to discover drivers of proliferative and invasive breast tumours,” said Xian Chen, PhD, professor in the UNC School of Medicine Department of Biochemistry & Biophysics. “We think that eventually, these tools could help doctors better predict which particular patients have a good response, or acquire resistance to treatment.” Doctors often rely on information about tumour size, whether the cancer has spread and the tumour subtype to make treatment decisions. In addition to clinical subtypes of breast cancer, researchers have discovered molecular subtypes that have been used to help make treatment decisions. However, Chen argues that existing markers do not adequately distinguish breast cancer patient sub-populations with different clinical outcomes.

“Single ‘omics’ approaches, which rely on either genomics, transcriptomics, or proteomics alone, fail to dissect the heterogeneity that contributes to individual patients’ variability in terms of their rates of tumour growth, metastasis, or susceptibility to anti-cancer therapies,” he said. “Because biomarkers are not available to distinguish distinct patient sub-populations that are either responsive or resistant to particular drugs, doctors do not have all the tools they need to predict patient response to treatment and outcomes.”
In their study, the researchers wanted to see if they could stratify patients beyond existing molecular subtypes. Their goal was to develop a method to determine which patients within a single subtype would develop resistance or invasive cancer. There are five major molecular subtypes of breast cancer, which are classified based on how genes are expressed in a tumour.

Chen and his colleagues analysed luminal breast cancer and basal-like breast cancer, which is more commonly known as triple negative breast cancer, using breast cancer samples from two large international studies, The Cancer Genome Atlas and the Molecular Taxonomy of Breast Cancer International Consortium.

To move beyond subtype for identifying exactly which patients might develop resistance, they first sorted the most invasive tumour cells in frozen tissue using a molecular probe that was able to distinguish tumour from adjacent non-malignant cells or tissue by binding to an epigenetic regulator, or a histone methylase, called G9a. This enzyme has been reported by other scientists to be abnormally upregulated in many cancer types, including breast cancer.

They then identified select proteins that were working with G9a as partners-in-crime, and worked backwards from there to identify the genetic abnormalities linked to those partner proteins in the cancer cell. They found in many instances the genes for these interactor proteins were amplified in multiple copies, or abnormally overexpressed, rather than mutated.

“Nowadays, people think somatic mutations of select genes are the primary drivers of tumorigenesis,” Chen said. “We didn’t see many mutations on our identified driver genes. We actually found the genes encoding those interactors have a high frequency amplification in breast cancer patients with poor prognosis.”

They then used this information to generate sets of genes that encoded these “interactor proteins,” and identified those linked to poor prognosis in patients. Looking ahead, Chen and his colleagues plan to determine the specificity and sensitivity of multi-omic aberrations of particular interactor gene sets as new systems biomarkers to predict cancer patient prognosis.

University of Northern Carolina

Researchers at the Bellvitge Biomedical Research Institute (IDIBELL) have just described for the first time the crucial involvement of a cell membrane protein in the development and progression of liver cancer.  This protein, called clathrin, is known for its key role in the process of internalization of molecules from the extracellular space into the cell, called endocytosis. In this process, the cell membrane folds creating vesicles with a cladded structure. Thanks to the new results, analysing the levels of clathrin expression in biopsies of hepatocellular carcinoma patients will help select those patients who will benefit from a much more targeted and personalized therapy.

The research team, led by Dr Isabel Fabregat, who is a professor at the Faculty of Medicine and Health Sciences of the University of Barcelona and a researcher at the CIBER of Hepatic and Digestive Diseases, has shown that liver cells with invasive features have high levels of clathrin, a protein whose involvement in liver cancer was unknown until now. Specifically, researchers showed that high expression levels of clathrin correlate with the activation of the pro-tumorigenic pathway of a known hepatic carcinogenesis actor: TGF-β. In this sense, the work provides completely new and clinically valuable knowledge when it comes to understanding the complex and controversial role of TGF-β in this type of cancer.

TGF-β, which belongs to a large group of proteins called cytokines, has a dual role:
in normal conditions, or in early stages of carcinogenesis, it plays a tumour suppressive role, promoting cell death and reducing tumour growth. But in advanced stages of liver cancer, where this signalling pathway is highly activated, tumour cells have acquired capabilities to escape its suppressor functions and respond to TGF-β by inducing cell migration and invasion, and thus contributing to tumour spreading.

Previous work by the Fabregat group had shown that for this change in cellular behaviour to take place, TGF-β activates the EGF receptor pathway (EGFR) in tumour cells, whose overexpression and hyperactivity has been associated with a large number of cancers. The new results have shown that clathrin is essential in the endocytosis of EGFR, a decisive step for the activation of this pathway by TGF-β. In vitro experiments of this recent work have allowed the IDIBELL researchers to demonstrate that clathrin cell levels determine, via EGFR, the function of TGF-β. If the expression of clathrin is eliminated, the cells die. On the contrary, high levels of clathrin promote the pro-invasive and tumorigenic character of the cells. The reason for this effect must be found in the functionality of the EGFR pathway: the elimination of clathrin results in an inhibition of this signalling pathway. Researchers have also shown that TGF-β is capable of inducing clathrin synthesis, ultimately encouraging a self-stimulation loop.

It is interesting to mention that the study also demonstrates that clathrin expression increases during hepatic tumorigenesis both in humans and mice, and its expression changes the response to TGF-β in favour of anti-apoptotic / pro-tumorigenic signals. There is a positive correlation between the expression of TGF-β and clathrin in samples of hepatocellular carcinoma patients. Patients expressing high levels of TGF-β and clathrin showed a worse prognosis and reduced survival. According to Dr. Fabregat, "determining the levels of clathrin expression in samples of hepato-cellular carcinoma patients can be of great help in selecting those who can be given a therapy based on inhibitors of the TGF-β  pathway”.

IDIBELL

Working with model mice, post-mortem human brains, and people with schizophrenia, researchers at the RIKEN Center for Brain Science in Japan have discovered that a subtype of schizophrenia is related to abnormally high levels hydrogen sulfide in the brain.
Experiments showed that this abnormality likely results from a DNA-modifying reaction during development that lasts throughout life. In addition to providing a new direction for research into drug therapies, higher than normal levels of the hydrogen sulfide-producing enzyme can act as biomarker for this type of schizophrenia.

Diagnosing disorders of thought is easier when a reliable and objective marker can be found. In the case of schizophrenia, we have known for more than 30 years that it is associated with an abnormal startle response. Normally, we are not startled as much by a burst of noise if a smaller burst – called a prepulse – comes a little bit earlier. This phenomenon is called prepulse inhibition (PPI) because the early pulse inhibits the startle response. In people with schizophrenia, PPI is lowed, meaning that their startle response is not dampened as much as it should be after the prepulse.

The PPI test is a good behavioural marker, and although it cannot directly help us understand the biology behind schizophrenia, it was the starting point that led to current discoveries.

The researchers at RIKEN CBS began first looked for differences in protein expression between strains of mice that exhibit extremely low or extremely high PPI.
Ultimately, they found that the enzyme Mpst was expressed much more in the brains of the mouse strain with low PPI than in the strain with high PPI. Knowing that this enzyme helps produce hydrogen sulfide, the team then measured hydrogen sulfide levels and found that they were higher in the low-PPI mice.

"Nobody has ever thought about a causal link between hydrogen sulfide and schizophrenia," says team leader Takeo Toshikawa. "Once we discovered this, we had to figure out how it happens and if these findings in mice would hold true for people with schizophrenia."

First, to be sure that Mpst was the culprit, the researchers created an Mpst knockout version of the low-PPI mice and showed that their PPI was higher than that in regular low-PPI mice. Thus, reducing the amount of Mpst helped the mice become more normal. Next, they found that MPST gene expression was indeed higher in postmortem brains from people with schizophrenia than in those from unaffected people. MPST protein levels in these brains also correlated well with the severity of premortem symptoms.
Now the team had enough information to look at MPST expression as a biomarker for schizophrenia. They examined hair follicles from more than 150 people with schizophrenia and found that expression of MPST mRNA was much higher than people without schizophrenia. Even though the results were not perfect-indicating that sulfide stress does not account for all cases of schizophrenia-MPST levels in hair could be a good biomarker for schizophrenia before other symptoms appear.

Whether a person develops schizophrenia is related to both their genetics and the environment. Testing in mice and postmortem brains indicated that high MPST levels were associated with changes in DNA that lead to permanently altered gene expression. So, the next step was for the team to search for environmental factors that could result in permanently increased MPST production.

Because hydrogen sulfide can actually protect against inflammatory stress, the group hypothesized that inflammatory stress during early development might be the root cause. "We found that anti-oxidative markers – including the production of hydrogen sulfide – that compensate against oxidative stress and neuroinflammation during brain development were correlated with MPST levels in the brains of people with schizophrenia," says Yoshikawa.

He proposes that once excess hydrogen sulfide production is primed, it persists throughout life due to permanent epigenetic changes to DNA, leading to "sulfide stress" induced schizophrenia.

EurekAlert