January 16, 2022

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Breast cancer brain metastasis depends on fatty acid synthesis

Nature Cancer: Breast cancer brain metastasis depends on fatty acid synthesis

 

Nature Cancer: Breast cancer brain metastasis depends on fatty acid synthesis.  Understanding the nutritional level of the environment and the characteristics of which nutrients limit the growth of different cancers in these environments can guide the treatment of metabolic-dependent cancers in different tissues.

Nature Cancer: Breast cancer brain metastasis depends on fatty acid synthesis

Solid tumor metastasis is closely related to the high mortality rate of cancer, and it is still a daunting challenge. Brain metastasis is particularly related to poor prognosis.

The advancement of human epidermal growth factor receptor 2 (HER2) targeted therapy has improved the condition of patients with HER2+ breast cancer. However, this disease is very difficult to control after metastasis to the brain because of the blood-brain barrier (BBB)/blood-brain tumor barrier (BTB) complicates the delivery of drugs to brain metastases. However, more and more evidences show that the microenvironment of brain tumors is also an important reason for the difficult treatment of brain metastases.


On April 1, 2021, a research team from Massachusetts General Hospital and Massachusetts Institute of Technology published a research paper titled “Fatty acid synthesis is required for breast cancer brain metastasis” in Nature Cancer.

The study found that when breast cancer cells spread to the brain, these cancer cells must promote fatty acid synthesis in order to survive in the new environment. The research team further discovered that fatty acid synthase (FASN) is a potential target for inhibiting breast cancer brain metastasis.

Nature Cancer: Breast cancer brain metastasis depends on fatty acid synthesis

In this study, the research team explored the different metabolic dependencies of primary and metastatic tumors to determine how the brain microenvironment affects the growth and metabolism of breast tumors. The human BT474 breast cancer orthotopic transplantation mouse model was used to simulate the clinical features of human HER2+  breast cancer brain metastasis. The metabolite analysis, gene expression analysis and 13C in vivo were performed on breast cancer tumors implanted in the mouse breast fat pad and brain. -Glucose tracing found that breast cancer growing in the brain showed an up-regulation of fatty acid synthesis relative to tumors growing in the breast fat pad.

Nature Cancer: Breast cancer brain metastasis depends on fatty acid synthesis

Breast cancer cells cultured in defatted medium showed enhanced glucose fatty acid synthesis, possibly reflecting the expected transcriptional response to lipid deficiency. Compared with standard culture conditions, the 13C-labeled palmitate isotopic distribution of breast cancer cells under lipid depletion conditions also changed, indicating that when these cells lack exogenous lipids, the contribution of glucose to acetyl-CoA increases .

In order to investigate whether the decrease in lipid availability in the brain tissue microenvironment can explain the changes in 13C markers in breast tumor tissue, the research team quantified the relative abundance of complex lipids in mouse cerebrospinal fluid (CSF) and plasma, and found that compared with plasma, The level of lipid species measured in the cerebrospinal fluid is much lower, which is consistent with the known clinical laboratory values ​​of humans, indicating that the decrease in the acquisition of lipids in the brain microenvironment compared with the primary site can be explained in brain breast tumors An increase in fatty acid synthesis is observed.

Nature Cancer: Breast cancer brain metastasis depends on fatty acid synthesis

To test the need for fatty acid synthesis in different environments and tissues, the research team used CRISPR-Cas9 gene editing to knock out fatty acid synthase (FASN) in breast cancer cells, further confirming that the reduction in fatty acid synthase (FASN) expression reduced fatty acids Synthesis and palmitate levels.

In summary, these data confirm that the expression of fatty acid synthase (FASN) is necessary for lipid synthesis and maintenance of palmitate levels, especially in the absence of exogenous lipids.

Understanding the nutritional level of the environment and the characteristics of which nutrients limit the growth of different cancers in these environments can guide the treatment of metabolic-dependent cancers in different tissues.

The genetic and pharmacological effects of fatty acid synthase (FASN) can inhibit the growth of breast cancer in the brain, indicating that fatty acid synthesis is necessary for the growth of brain breast tumors, supporting fatty acid synthase (FASN) as a potential therapeutic target for breast cancer brain metastasis.

 

(source:internet, reference only)


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