Acetate helps hypoxic cancer cells get fat


CRUK_JurreKamphorst_21514_webToday’s guest blog is a Cancer Research UK Career Development Fellow, Jurre Kamphorst, a researcher focusing on the metabolic stress responses in cancer cells and lead author of a study published in Cancer & Metabolism.

Unlike normal cells, cancer cells are wired to just keep on growing. This continued growth requires a constant supply of cellular building blocks, including fatty acids for cell membranes. Normally, fatty acids are mostly being made from glucose. However, tumors often face reduced oxygen levels (hypoxia), causing glucose to be only partially metabolized and secreted as lactate, instead of being used for fatty acid synthesis. We discovered that acetate substitutes for glucose as a source for fatty acid synthesis in hypoxic cancer cells.

We were initially interested in learning more about fatty acid metabolism as a function of oncogene expression and oxygen availability. Therefore, we developed an assay to measure fatty acids with mass spectrometry. A key aspect is that we feed cultured cancer cells stable-isotope labeled versions of the primary nutrients, glucose and glutamine.

Their carbons are heavier than normal glucose and glutamine. By ‘tracing’ these heavy carbons in the fatty acids, we can tell what fraction of the cellular fatty acids were made by the cells versus that which is taken up from the medium in which the cells are bathed.

We were performing analyses on hypoxic cancer cells, because we had reason to believe they were relying more on uptake of fatty acids than normal cells, when we noticed something peculiar. Our method allows us to determine where the fatty acid precursor, acetyl-CoA, is derived from, and we found that quite a considerable fraction was not coming from glucose or glutamine, in hypoxia, but from something else.

After testing various potential candidates, we found that the mystery source is acetate. All cancer types show increased use of acetate in hypoxia, and our preliminary findings indicate that colorectal, breast, and pancreatic cancers, in particular, are avid acetate consumers.

Prior to our study there already was some interest in exploiting acetate as a diagnostic marker for cancer using PET imaging. We now provide a solid biochemical basis for this approach and we predict that hypoxic cancers are amenable to this type of screening.

Acetyl-CoA synthetase 2 (ACSS2) is the enzyme converting acetate into acetyl-CoA, and its inhibition may slow or even stop tumor growth. Articles will soon be published by the labs of Eyal Gottlieb and Steve McKnight, demonstrating that inhibition of ACSS2 indeed has anti-tumor effects. The development of new drugs against ACSS2 is already under way.

To learn how ACSS2 is best inhibited and in what condition(s) its inhibition will be particularly effective, more fundamental research will be necessary. To this end we are quite interested in quantifying, in more detail, the contribution of acetate to fatty acid metabolism and its importance relative to glutamine and fatty acid import (two other, recently reported precursors for cancer fatty acids). It is still unclear if induction of ACSS2 activity is caused by increased enzyme abundance, by some form of enzyme modification, or both. Consequently, there is much still to be learned about how ACSS2 activity is regulated.

We are very excited about our discovery of the role of acetate in hypoxic cancer cells. It shows that there is still much to learn about fundamental aspects of cancer metabolism and we are hopeful that this will lead to drugs against cancer.


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