Cancerous tumours must be fed. Their unregulated growth requires a steady stream of blood flow and nutrients. Thus, one way that researchers have tried to wipe out cancer is to target cells undergoing the metabolic shifts that enable a tumour’s rapid growth.

Yet new findings from University of Pennsylvania researchers suggest that such efforts might have missed a key pathway that enables the changes in metabolism that benefit tumours. Their work finds that mitochondrial stress alone can trigger metabolic shifts through a pathway that involves p53, a protein widely known to play multiple important roles in cancer.

“In all five cancer cell lines we looked at, we saw that p53 was induced when mitochondrial function was affected,” said senior author Narayan Avadhani, the Harriet Ellison Woodward Professor of Biochemistry in Penn’s School of Veterinary Medicine’s Department of Biomedical Sciences. “This led to our discovery that it’s possible to promote tumour growth independent of the HIF-1α pathway, which had up to this point been a prime target of therapeutic interventions.”

The study points to a new factor that could inform our understanding of how cancer progresses. It’s possible that markers of metabolic stress could even serve as a biomarker for a cancer’s aggressiveness or likelihood to spread.

Avadhani teamed with Penn Vet’s Anindya Roy Chowdhury, the lead author and a research associate, and Serge Y. Fuchs, professor of cell biology, as well as Ph.D. student Apple Long and Anil Rustgi, the T. Grier Miller Professor of Gastroenterology, both of Penn’s Perelman School of Medicine. Avadhani and Fuchs are also members of Penn Vet’s Mari Lowe Center for Comparative Oncology Research.

Mitochondrial stress induces expression of nearly 120 genes involved in cell metabolism.
In earlier studies, Avadhani and colleagues had shown that disrupting mitochondria could lead to tumour growth. Mitochondria are often referred to as the “powerhouses” of cells because they produce ATP, the molecular energy currency that cells utilize to perform their diverse functions. In related work, the researchers had also observed that subjecting mitochondria to stress also triggered an increase in p53 but, until now, hadn’t conducted follow-up on that finding.

Because p53 is mutated in nearly 50 percent of human cancers, it is widely believed to have a tumour-suppressor function. The researchers decided to take a more detailed look into the connection between mitochondrial stress and p53.

They experimentally depleted mitochondrial DNA to induce mitochondrial stress in six cell lines, including several cancer cell lines, and found that p53 levels increased in response to the mtDNA depletion in each type of cell. Because HIF-1α activity is known to play both complementary and contradictory roles in cancer to p53, they next looked to see how that protein responded. They found that p53 inhibited HIF-1α activity.

Looking specifically at a human colon cancer cell line in which p53 was experimentally deleted, they again found a relationship with HIF-1α: Its activity was six-times higher in the colon cancer cell line with p53 depleted than in the wild type colon cancer cell line, a further indication that p53 inhibits HIF-1α.

To ensure that this was not strictly associated with depletion of mitochondrial DNA, the researchers induced mitochondrial stress using other means, including with chemicals agents and by disrupting the membrane, and found that all induced p53.

Further investigation revealed that p53 reduced HIF-1α levels in the nucleus and the cytoplasm of cells and that genes responsive to HIF-1α were blunted when mitochondrial DNA was depleted. Notably, they found that the expression of several genes involved with glycolysis, a metabolic process by which cells break down sugar to make energy, jumped dramatically in cells in which mtDNA was depleted. Some of these were the same genes that HIF-1α normally regulates, pointing to mitochondrial stress as a similar but completely separate pathway by which a metabolic shift can occur in cancer cells.

Finally, the team demonstrated that, in cells with depleted mtDNA, p53 physically interferes with HIF-1α by preventing it from binding to gene promoters that it would normally and by promoting ubiquitination of HIF-1α, a process that tags the protein for degradation in the cell.

The findings point to a new direction and possible new targets for preventing the metabolic shift that can foster a supportive environment for cancer growth.

Penn’s School Veterinary Medicine www.vet.upenn.edu/about/press-room/press-releases/article/penn-team-finds-mitochondrial-stress-induces-cancer-related-metabolic-shifts

Ribonucleic acid (RNA) binding fluorescent probes have been powerful and important analytical tools for the study of RNA structures and functions.

A research group led by Professor Seiichi Nishizawa at Tohoku University’s Graduate School of Science has reported a new RNA probe that binds to double-stranded RNA (dsRNA) in a sequence-specific manner.

The probe has a weak response to mismatch-containing dsRNA sequences, thus enabling sequence-selective fluorescence sensing of dsRNA at the single-base pair resolution. It also shows a preference for binding with dsRNA over dsDNA, which is an important selective process for future applications in a cellular environment where RNA and DNA co-exist.

In contrast to the conventional analytical method which is limited to single-stranded regions of RNA, the new analytical method allows for fluorescent sensing of target dsRNA structure and sequence for the first time.

It is expected that the probe will open up new possibilities for analysing the functions of dsRNA-containing structures, which are closely related to various biological phenomena and diseases.

Tohoku University www.tohoku.ac.jp/en/press/fluorescence_detection_of_rna.html

The first patient was a mystery.

Arriving at Duke six years ago at the age of three, the youngster had mild developmental delays and physical characteristics that included a large body and large head circumference. A genetic analysis showed mutation of a specific gene, known as ASXL2, which had never been singled out as causing disease.

The youngster’s doctor, Vandana Shashi, a professor of paediatrics for the Division of Medical Genetics at Duke University School of Medicine, told his parents their son likely had a rare and yet-unidentified disease. And she promised to remain vigilant if any other cases popped up in the medical literature that might provide additional clues.

After none turned up, Shashi set out to see if the mystery case might be solved, instead, using the tools of the Undiagnosed Diseases Network (UDN) at the National Institutes of Health, which links Duke and six other medical teaching sites around the country. The participating centres pool information and innovations about diseases that are so rare they often stump the broader medical community.

Within just six weeks — connected to other UDN research labs and an international database of genes and disease characteristics called GeneMatcher — Shashi had a remarkable trove: Five additional children, all with the same physical features and the ASXL2 gene mutation.

“We can now definitively say this is a newly identified disease,” Shashi said. “With just one case, we could not say the gene mutation was the underlying cause. But with six cases, all with the same ASXL2 mutation, it is definitive.”

The new disease, which still has no name, does have similarities to two other rare genetic disorders arising from related genes. A condition called Bohring-Opitz syndrome is the result of a mutation of the ASXL1 gene, while Bainbridge-Ropers syndrome is caused by a flaw in the ASXL3 gene. Both conditions are also rare, and result in similar, but more severe impairments.

It’s unknown how the ASXL2 genetic mutation arises, but Shashi said identifying the root cause of the children’s condition is a first step, and could help drive new therapies and treatment approaches.

The immediate benefit is to the families of the children, who now have an answer to their most basic question.

“It has been wonderful to be connected to other families who share this genetic condition,” said Teresa Locklear, whose son, Issac, was the first patient to present with the mutation at Duke. “When we started, we hoped we would find other families with children who were older than Isaac, to provide a sort of roadmap for what to expect. But it turns out, Isaac is the oldest and we are the ones sharing our experiences with parents of younger children, and that’s been so rewarding.”

Study co-author Loren del Mar Peña, assistant professor in the Department of Pediatrics at Duke, said reducing isolation for families with a rare disease has tremendous impact.

“These families feel truly alone when their child clearly has a disorder, and yet there is no name for it, and no community of people they can relate to with shared experiences,” Peña said. “This will help them be able to connect with others and compare notes. That’s a huge deal – to know you aren’t the only one and there a five other children out there.”

Duke University corporate.dukehealth.org/news-listing/network-and-gene-tools-help-quickly-identify-new-rare-genetic-disease

Skin cancer is the most common of all cancers, and melanoma, which accounts for 2% of skin cancer cases, is responsible for nearly all skin cancer deaths. Melanoma rates in the U.S. have been rising rapidly over the last 30 years, and although scientists have managed to identify key risk factors, melanoma’s modus operandi has eluded the world of medical research.

A new Tel Aviv University study sheds light on the trigger that causes melanoma cancer cells to transform from non-invasive cells to invasive killer agents, pinpointing the precise place in the process where “traveling” cancer turns lethal. The research was led by Dr. Carmit Levy of the Department of Human Genetics and Biochemistry at TAU’s Sackler School of Medicine and conducted by a team of researchers from TAU, the Technion Institute of Technology, the Sheba Medical Center, the Institut Gustave Roussy and The Hebrew University of Jerusalem.

If melanoma is caught in time, it can be removed and the patient’s life can be saved. But once melanoma invades the bloodstream, turning metastatic, an aggressive treatment must be applied. When and how the transformation into aggressive invasion takes place was a mystery until now.

‘To understand melanoma, I had to obtain a deep understanding about the structure and function of normal skin,’ said Dr. Levy, ‘Melanoma is a cancer that originates in the epidermis, and in its aggressive form it will invade the dermis, a lower layer, where it eventually invades the bloodstream or lymph vessels, causing metastasis in other organs of the body. But before invading the dermis, melanoma cells surprisingly extend upward, then switch directions to invade.

‘It occurred to me that there had to be a trigger in the microenvironment of the skin that made the melanoma cells ‘invasive,” Dr. Levy continued. ‘Using the evolutionary logic of the tumour, why spend the energy going up when you can just use your energy to go down and become malignant?’

After collecting samples of normal skin cells and melanoma cells from patients at hospitals around Israel, the researchers mixed normal and cancerous cells and performed gene analysis expression to study the traveling cancer’s behaviour. They found that, completely independent of any mutation acquisition, the microenvironment alone drove melanoma metastasis.

‘Normal skin cells are not supposed to ‘travel,” said Dr. Levy. ‘We found that when melanoma is situated at the top layer, a trigger sends it down to the dermis and then further down to invade blood vessels. If we could stop it at the top layer, block it from invading the bloodstream, we could stop the progression of the cancer.’

The researchers found that the direct contact of melanoma cells with the remote epidermal layer triggered an invasion via the activation of ‘Notch signalling,’ which turns on a set of genes that promotes changes in melanoma cells, rendering them invasive. According to the study, when a molecule expressed on a cell membrane — a spike on the surface of a cell, called a ligand — comes into contact with a melanoma cell, it triggers the transformation of melanoma into an invasive, lethal agent.

‘When I saw the results, I jumped out of the room and shouted, ‘We got it!” Dr. Levy said. ‘Now that we know the triggers of melanoma transformation and the kind of signalling that leads to that transformation, we know what to block. The trick was to solve the mystery, and we did. There are many drugs in existence that can block the Notch signalling responsible for that transformation. Maybe, in the future, people will be able to rub some substance on their skin as a prevention measure.’ Tel Aviv University

Siemens Healthineers will expand the company’s existing manufacturing operations in Shanghai, China to include a new in vitro diagnostics facility. The China manufacturing facility will enable in-country manufacturing capabilities for clinical chemistry and immunoassay reagents. “This investment demonstrates the company’s continued commitment to address the evolving needs in the Chinese market and in healthcare markets across the globe,” said Franz Walt, President, Laboratory Diagnostics, Siemens Healthineers. China is the second largest market for Siemens Healthineers. According to George Chan, President, Greater China, Siemens Healthineers, “The opening of this facility strengthens our ability to support Chinese healthcare reform as we deliver better outcomes at a lower cost to our customers.” The company expects to employ hundreds of additional employees once the project is completed.

www.healthcare.siemens.com