What exactly did you find?
Sarah-Maria: We discovered that the use of fatty acids as nutrients has a much greater impact on the proliferation of endothelial cells than previously suspected. We found this by inhibiting the fatty acid breakdown via knocking down the enzyme CPT1a, an enzyme that is important for the transport of fatty acids to the mitochondria. To our amazement, this did not result in decreased energy production, which is a known role of fatty acid breakdown. However, it resulted in a loss of production of deoxyribonucleotides.
In biochemistry textbooks, the current dogma is that while the energy production resulting from the oxidation of fatty acid breakdown products contributes to the buildup of macromolecules such as DNA, the carbon backbone is mostly provided by sugars and some amino acids. Yet, we show for the first time that carbon from fatty acids is important in sustaining deoxyribonucleotide production and thus DNA synthesis in endothelial cells.
“This is an indication that blocking fatty acid breakdown could constitute a possible therapeutic avenue in the fight against cancer.”Peter Carmeliet
Peter: This could definitely be an important new strategy that needs further research. Current anti-angiogenic treatments target the known angiogenic factors. However, these therapies are not perfect, because cancer cells find a way of producing a different angiogenic factor and are therefore able to stimulate blood vessel formation. We recently showed that glycolysis (sugar metabolism) in endothelial cells plays an essential role in angiogenesis, which made us believe that starving endothelial cells might be an alternative strategy. And now we know that this might be feasible by attacking the fatty acid metabolism.
We already studied the therapeutic potential of a pharmacological blocker of fatty acid transport to the mitochondria (etomoxir) in mouse models. These mice exhibit remarkably less pathological blood vessel formation. This is an indication that blocking fatty acid breakdown could constitute a possible therapeutic avenue in the fight against cancer. It could also be used to treat diseases such as macular degeneration, a disease where new blood vessel formation in the eyes results in blindness. However, many more years of research are required to confirm these results.
“By inviting the very top experts, we hope to enthuse the scientific community about this exciting branch of biomedical research.”
You are both involved in the organization of the VIB conference “Metabolism in Cancer and Stromal Cells” in September in Leuven. Can you tell us – as a kind of promotional talk – why we should definitely be there?
Peter: For the past 10 years, there has been a renewed interest in cancer cell metabolism, but the metabolism of endothelial cells and other stromal cells has been largely overlooked. Cancer and stromal cell metabolism is a booming field, impacting numerous (patho)-biological processes, ranging from cancer, inflammation, immunology to neurobiology and neurodegeneration. Importantly, emerging evidence indicates that several metabolic enzymes are druggable targets, thus offering unprecedented translational opportunities for new treatment paradigms.
Sarah-Maria: For me it has been fantastic to be part of the revolutionary, dynamic field of cancer metabolism and to see now the first compounds from the recent endeavors in clinical trials. Yet, the importance of metabolism does not stop with the cancer cells but beyond them basically impacts any cell. Nowadays, the concepts of studying cancer metabolism have been applied also to elucidate stromal cell metabolism during disease, yielding groundbreaking insights with therapeutic potential. Thus, by organizing a conference covering cancer and stromal cell metabolism with key researchers from both fields we provide a unique opportunity of exchange and interaction.
How important is it to organize such a conference here? Why are you doing this?
Peter: Metabolism is a rapidly growing field, and an increasing number of groups in and outside VIB have become captivated by its enormous potential. Therefore, it is about time that VIB organizes this meeting. By inviting the very top experts, we hope to enthuse the scientific community about this exciting branch of biomedical research.
Sarah-Maria: Worldwide, there are key research groups doing fantastic work on disease-related metabolic alterations. Yet, most scientific meetings on metabolism still take place in the US, but there is a growing community of scientists in Europe and at VIB who are excited about the potential of targeting metabolism for therapy. Thus, with this conference we want to launch an internationally recognized and internationally attended conference series to further boost the aspiring research on metabolism in Europe and at VIB.
For more info about
‘Metabolism in Cancer and Stromal Cells’