Neuro-oncologists discover cancer cells can burn acetate for fuel.


UT Southwestern Medical Center researchers have discovered that brain tumours are capable of burning acetate for fuel, providing a new potential target for halting tumour growth.  The opensource study is published in the journal Cell.

The medical community are currently investigating what fuels cancer cell growth. For more than 75 years, researchers have known that cancer cells use glucose as the major fuel, but efforts to halt cancer growth by controlling glucose levels in the brain haven’t worked.

The team identified that glucose wasn’t the only fuel being burned.  Acetate can be used to generate fuel and metabolites that can then be used to make other things that the cell needs to survive and multiply.

The current study employed specially engineered mouse models so that the tumours grown in the brain were very similar to human tumours, especially with respect to the molecular and metabolic characteristics. They then infused both 13C-acetate and 13C-glucose into the mice and were able to show that the tumours burn acetate as fuel.

This is the first demonstration of acetate being used by the cell in this way. The striking finding was that all cancers the group studied had the same ability to burn acetate.  All the tumours studied increased expression of ACSS2, the acetate metabolizing enzyme, and the gliomas appear to be dependent on acetate for growth.

The researchers then validated their findings in two patients with glioblastomas and two patients with brain metastases (breast and lung cancer) who were undergoing surgical resection of their tumours.  The analysis showed that the human tumours robustly burned acetate.  ACSS2 may thus be a therapeutic target for these very aggressive tumours that have limited therapies available.

The team summise that the insights provided by the current study position acetate metabolism as a potentially exploitable vulnerability in cancer metabolism.

Source:  UT Southwestern Medical Center

 

Glioblastomas and brain metastases are highly proliferative brain tumors with short survival times. Previously, using 13C-NMR analysis of brain tumors resected from patients during infusion of 13C-glucose, we demonstrated that there is robust oxidation of glucose in the citric acid cycle, yet glucose contributes less than 50% of the carbons to the acetyl-CoA pool. Here, we show that primary and metastatic mouse orthotopic brain tumors have the capacity to oxidize [1,2-13C]acetate and can do so while simultaneously oxidizing [1,6-13C]glucose. The tumors do not oxidize [U-13C]glutamine. In vivo oxidation of [1,2-13C]acetate was validated in brain tumor patients and was correlated with expression of acetyl-CoA synthetase enzyme 2, ACSS2. Together, the data demonstrate a strikingly common metabolic phenotype in diverse brain tumors that includes the ability to oxidize acetate in the citric acid cycle. This adaptation may be important for meeting the high biosynthetic and bioenergetic demands of malignant growth.  Acetate Is a Bioenergetic Substrate for Human Glioblastoma and Brain Metastases.  Bachoo et al 2014.

Glioblastomas and brain metastases are highly proliferative brain tumors with short survival times. Previously, using 13C-NMR analysis of brain tumors resected from patients during infusion of 13C-glucose, we demonstrated that there is robust oxidation of glucose in the citric acid cycle, yet glucose contributes less than 50% of the carbons to the acetyl-CoA pool. Here, we show that primary and metastatic mouse orthotopic brain tumors have the capacity to oxidize [1,2-13C]acetate and can do so while simultaneously oxidizing [1,6-13C]glucose. The tumors do not oxidize [U-13C]glutamine. In vivo oxidation of [1,2-13C]acetate was validated in brain tumor patients and was correlated with expression of acetyl-CoA synthetase enzyme 2, ACSS2. Together, the data demonstrate a strikingly common metabolic phenotype in diverse brain tumors that includes the ability to oxidize acetate in the citric acid cycle. This adaptation may be important for meeting the high biosynthetic and bioenergetic demands of malignant growth. Acetate Is a Bioenergetic Substrate for Human Glioblastoma and Brain Metastases. Bachoo et al 2014.

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