Nav: Home

A single molecule is missing and the cell world is empty

June 12, 2017

Cells multiply by duplicating themselves: they grow, replicate their components, and finally split into two. Many diseases are related to defective cell division; cancer is one of them. Understanding mechanisms conducting this division is therefore essential in the search for cancer treatments. Researchers at the University of Geneva (UNIGE), Switzerland, in collaboration with the IMBA- Institute of Molecular Biotechnology at the Vienna BioCenter (VBC) and the Weill Cornell Medical College in New York, have turned their attention in particular to the role of ESCRT proteins, which are responsible for severing cell membranes. These proteins assemble in spirals that gradually bring about cleavage of the membrane, spirals that are constantly renewing themselves with the help of the Vps4 molecule. Without this molecule the renewal stops, eventually preventing the membrane from being severed. This research, reported in the journal Nature Cell Biology, sheds new light on the fight against cancer and HIV, both of which depend on cell division.

In a previous research, the team led by Professor Aurélien Roux of the Department of Biochemistry at the Faculty of Sciences of the UNIGE, discovered that ESCRT proteins assemble in the form of spirals, a structure that is unique amongst the many forms created by the organism's filamentous proteins. Why this unique form? During cell division, the cell contracts at its centre to separate the two daughter cells. At the end of this stage, called cytokinesis, a very thin link remains between the cells, a tube of plasma membrane - the cell's skin - called the "cytoplasmic bridge". The spirals formed by ESCRT proteins coil around the inner surface of this tube and constrict it in order to sever it, a stage called abscission. Professor Roux's team showed that these spirals behaved like the springs of a watch, suggesting a scenario wherein the more the ESCRT proteins assembled, the more tightly they were compressed.

Research conducted simultaneously in vitro and in vivo

After discovering why these molecules assembled in spirals, the UNIGE researchers examined the dynamics of the assembly. Until now scientists have thought that they assembled like Lego blocks, the proteins being added progressively to the structure without ever leaving it. In this new study, biochemists were able to invalidate this hypothesis. To do so they joined forces with the Gerlich group at IMBA, Vienna Biocenter, to conduct the experiment simultaneously in vivo (the Viennese scientists' part) and in vitro (the Genevan scientists' part).

"On our side, we observed the dynamics of the ESCRT proteins by isolating them on a flat artificial membrane that we created using lipids, onto which we placed the ESCRT protein complexes," explains Nicolas Chiaruttini, a research scientist at UNIGE. "And contrary to what we thought, the proteins do not form a rigidly fixed spiral that is compressed; instead there is a constant renewal of proteins, creating supple, mobile spirals in constant motion." Using a new imaging technique, the team led by Simon Scheuring in New York, working in collaboration with the UNIGE team, was able to directly visualize the dynamics and flexibility of these spirals. Conducting further research, the biochemists noted that this renewal cannot occur without the Vps4 molecule, which is an integral part of ESCRT protein complexes. "Vps4 is known for disassembling molecules in polymeric structures," says Aurélien Roux. "So it is the indispensable ingredient for the severing of membranes insofar as it enables the renewal of spirals."

It is worthwhile noting that the Viennese researchers reached exactly the same conclusions. "During our observations in the cell in motion, Vps4 was revealed to be necessary for the renewal of spirals," explains Beata Mierzwa, a researcher at IMBA-VBC. More importantly, the team observed that the absence or inactivation of Vps4 inhibited cell division in 50% of cases and delayed it significantly in the other 50%. Vps4 and the constant renewal of ESCRTs appear, therefore, to be essential for abscission. "It is rare to be able to conduct experiments in vivo and in vitro simultaneously, and the fact that the results coincide firmly establishes our study."

Another way to approach cancer and HIV

Cancer is characterized by excessive multiplication of diseased cells. By elucidating the role of the Vps4 molecule in cell division, researchers have decipher mechanisms that could be targeted as new treatments that would, for instance, block ESCRT protein renewal directly, thereby preventing the proliferation of the disease. Similarly, when a cell is infected by the Human Immunodeficiency Virus, virus particles bud from the membrane, then eventually break off from it to infect other cells. The virus must also sever the cell membrane in order to be released and spread the disease--a stage that is also carried out by ESCRT proteins. Here again, targeting the Vps4 molecule could prevent the virus from leaving the infected cell.

The primary role of fundamental research is not to find new drugs for cancer or AIDS traitements, but rather, by understanding how ESCRT and Vps4 participate in cell division and virus replication, "to provide knowledge essential to treat those diseases, and clues about potential interactions between treatments", concludes Aurélien Roux.

Université de Genève

Related Cancer Articles:

Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Cancer genomics continued: Triple negative breast cancer and cancer immunotherapy
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Metabolite that promotes cancer cell transformation and colorectal cancer spread identified
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
UH Cancer Center researcher finds new driver of an aggressive form of brain cancer
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
UH Cancer Center researchers develop algorithm to find precise cancer treatments
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
New analytical technology to quantify anti-cancer drugs inside cancer cells
University of Oklahoma researchers will apply a new analytical technology that could ultimately provide a powerful tool for improved treatment of cancer patients in Oklahoma and beyond.
Radiotherapy for lung cancer patients is linked to increased risk of non-cancer deaths
Researchers have found that treating patients who have early stage non-small cell lung cancer with a type of radiotherapy called stereotactic body radiation therapy is associated with a small but increased risk of death from causes other than cancer.
Cancer expert says public health and prevention measures are key to defeating cancer
Is investment in research to develop new treatments the best approach to controlling cancer?
UI Cancer Center, Governors State to address cancer disparities in south suburbs
The University of Illinois Cancer Center and Governors State University have received a joint four-year, $1.5 million grant from the National Cancer Institute to help both institutions conduct community-based research to reduce cancer-related health disparities in Chicago's south suburbs.
Leading cancer research organizations to host international cancer immunotherapy conference
The Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research will join forces to sponsor the first International Cancer Immunotherapy Conference at the Sheraton New York Times Square Hotel in New York, Sept.

Related Cancer Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Digital Manipulation
Technology has reshaped our lives in amazing ways. But at what cost? This hour, TED speakers reveal how what we see, read, believe — even how we vote — can be manipulated by the technology we use. Guests include journalist Carole Cadwalladr, consumer advocate Finn Myrstad, writer and marketing professor Scott Galloway, behavioral designer Nir Eyal, and computer graphics researcher Doug Roble.
Now Playing: Science for the People

#530 Why Aren't We Dead Yet?
We only notice our immune systems when they aren't working properly, or when they're under attack. How does our immune system understand what bits of us are us, and what bits are invading germs and viruses? How different are human immune systems from the immune systems of other creatures? And is the immune system so often the target of sketchy medical advice? Those questions and more, this week in our conversation with author Idan Ben-Barak about his book "Why Aren't We Dead Yet?: The Survivor’s Guide to the Immune System".