Lipid, also known as fat, is an optimal energy source and an important cell component. Much is required for the rapid and uncontrolled growth of cancer cells. Researchers from the Biozentrum of the University of Basel and from the University of Geneva have now discovered that the protein mTOR stimulates the production of lipids in liver tumors to satisfy the increased nutrient turnover and energy needs of cancer cells among other functions. This process has also been observed in patients with liver cancer as the scientists report in “Cancer Cell”.
In Switzerland, about 650 new cases of liver cancer are diagnosed every year. The incidence of the malignant and aggressive liver cell carcinoma has doubled in the last 20 years, especially in developed countries. One possible reason for this is the increase in obesity and diabetes.
The scientists led by Prof. Michael N. Hall at the Biozentrum, University of Basel, and Prof. Howard Riezman, University of Geneva, have gained new insights into tumor development and disease progression.
In mouse models and patient samples, they have demonstrated that the growth regulator mTOR – mammalian target of rapamycin – promotes de novo lipid synthesis and thus tumorigenesis. The accumulation of fatty acids and lipids in the liver is one of the major causes of hepatocellular carcinoma.
The liver: Detoxifier and energy supplier
“The liver is in a way our body’s kitchen,” explains Yakir Guri, medical doctor and first author of the study. “It stores and recycles nutrients, produces hormone precursors and detoxifies the body by eliminating harmful substances, such as drugs and alcohol.” Not only excessive alcohol consumption, but also obesity and diabetes combined with lack of exercise can damage the liver.
A first asymptomatic syndrome is so-called “fatty liver”, which may cause inflammation that can progress to hepatocellular carcinoma (HCC). The aggressive and rapidly proliferating HCC cells ultimately destroy the surrounding healthy liver tissue, leading to liver failure.
Hepatocellular carcinoma: mTOR activation promotes tumorigenesis
The researchers initially investigated the progression of the disease in a mouse model. For this purpose, they constitutively activated mTOR specifically in liver cells. “We already knew that mTOR is involved in tumor development as it centrally controls cell growth. However, in the case of HCC we did not know which downstream metabolic and signaling pathways are affected,” says Guri.
The researchers have now discovered that mTORC2 – mTOR forms two protein complexes termed mTORC1 and mTORC2 – promotes the new synthesis of fatty acids and certain lipids. Most people do not realize that our body contains more lipid species than genes. It is assumed that there are thousands of different types,” says Guri. “Together with Howard Riezman’s team, we have been able to analyze a broad spectrum of such lipids.”
Lipids: Synthesis of lipids is required for tumor development
In hepatocytes, mTORC2 stimulates in particular the production of two lipid species important for cell growth: sphingolipids and cardiolipins. The first are structural components of cell membranes, which have to be continuously supplied in rapidly proliferating cells. Cardiolipins are located in the cellular powerhouse, the mitochondria, and are involved in energy production. By enhancing cardiolipin synthesis, the energy-hungry tumor cells ensure their energy supply. “Cancer cells depend on the new synthesis of fatty acids and lipids; if you turn off the tap, you stop the development of tumors.”
Patients: Analysis of liver biopsies confirms correlation
Analysis of tissue samples from patients with HCC confirmed the observations made in the mouse model. mTORC2 and its signaling pathways, which promote de novo synthesis of fatty acids and lipids, are also activated in tumor samples from patients.
Thus, the protein complex plays a critical role in the progression of benign “fatty liver” to aggressive HCC. The study provides important insights for the development of potential therapeutic interventions, as it shows that targeted lipogenesis inhibitors may have the potential to prevent tumor development.
The project has been funded by the European Research Council (ERC), the Swiss Cancer Research Foundation and the Swiss National Centre of Competence in Research (NCCR) Chemical Biology.
Yakir Guri, Marco Colombi, Eva Dazert, Sravanth K. Hindupur, Jason Roszik, Suzette Moes, Paul Jenoe, Markus H. Heim, Isabelle Riezman, Howard Riezman and Michael N. Hall
mTORC2 promotes tumorigenesis via lipid synthesis
Cancer Cell (2017), doi: 10.1016/j.ccell.2017.11.011
• Prof. Michael Hall, University of Basel, Biozentrum, phone +41 61 207 21 50, email: email@example.com
• Dr. Katrin Bühler, University of Basel, Biozentrum, Communications, phone +41 61 207 09 74, email: firstname.lastname@example.org
Dr. Katrin Bühler | Universität Basel
More genes are active in high-performance maize
19.01.2018 | Rheinische Friedrich-Wilhelms-Universität Bonn
How plants see light
19.01.2018 | Albert-Ludwigs-Universität Freiburg im Breisgau
On the way to an intelligent laboratory, physicists from Innsbruck and Vienna present an artificial agent that autonomously designs quantum experiments. In initial experiments, the system has independently (re)discovered experimental techniques that are nowadays standard in modern quantum optical laboratories. This shows how machines could play a more creative role in research in the future.
We carry smartphones in our pockets, the streets are dotted with semi-autonomous cars, but in the research laboratory experiments are still being designed by...
What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...
For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.
Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...
At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.
No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...
Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.
Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...
08.01.2018 | Event News
11.12.2017 | Event News
08.12.2017 | Event News
19.01.2018 | Materials Sciences
19.01.2018 | Health and Medicine
19.01.2018 | Physics and Astronomy