STTT: Liu Zhihua/Wu Nan revealed that lipid metabolism plays an important role in the process of cancer metastasis

Although it is recognized that cancer cells survive and multiply by recombinant lipid metabolism, the role of lipid metabolism in metastasis remains unclear
.

On October 24, 2022, Liu Zhihua of the Chinese Academy of Medical Sciences and Peking Union Medical College and Wu Nan of Peking University jointly communicated on Signal Transduction and Targeted Therapy IF=38) published online entitled "Dysregulated ceramides metabolism by fatty acid 2-hydroxylase exposes a metabolic vulnerability to target cancer metastasis" The research showed that dysregulation of ceramide metabolism induced by fatty acid 2-hydroxylase exposes metabolic vulnerabilities
to targeted cancer metastasis.
The study used esophageal squamous cell carcinoma (ESCC) as a lung metastasis model and found fatty acid 2- that catalyzes hydroxylation of free fatty acids (FAs) in a subset of ESCC cells with high metastatic potential Hydroxylase (FA2H) is enriched, while a decrease in FA2H significantly reduces metastatic lesions
.

In addition, increased FA2H expression was positively correlated
with poor survival in patients with ESCC.
Lipidomic analysis found that two dihydroceramides – Cer (d18:0/24:0) and Cer (d18:0/24:1) were increased in FA2H-depleted metastatic ESCC cells
。 After dosing, Cer (d18:0/24:0) and Cer (d18:0/24:1) impair the formation
of pronounced metastasis in an experimental metastatic model in mice.

Due to the metabolically dependent nature of metastasis, intervention in the function of dysfunctional proteins in key metabolic processes can prevent and/or treat metastasis
in cell line-derived or patient-derived xenograftoma models.
Recent studies have reported that monocarboxylic acid transporter 1 (MCT1), which transports extracellular lactic acid to tumor cells, increases circulating melanoma cells and promotes the formation
of metastatic lesions.
When the MCT1 inhibitor AZD3965 was administered to mouse and patient-derived melanoma models, the metastatic potential of melanoma cells was significantly impaired without affecting subcutaneous growth
at the primary site.
Although a growing body of evidence highlights the unique metabolic properties of metastatic cancer cells, the link between metabolism and metastatic formation is not fully understood
.

Lipids are generally divided into fatty acids (FAs), triacylglycerol, glycerophospholipids, sphingolipids, and steroids, which are necessary
for building biofilms, storing energy, and transmitting signals, respectively.
In recent years, the dysfunction of lipid metabolism during tumorigenesis and development has attracted more and more attention
.
Key enzymes for lipid uptake, de novo synthesis, and catabolism are abnormally overexpressed or overactivated in different cancer types, thereby maintaining tumor cell growth, invasion, and metastasis
.
CD36, also known as FA transduction proteases, delivers polyunsaturated fatty acids into cells, and their increased expression indicates a poor
prognosis for cancer patients.
Mechanically, CD36 is enriched in metastasis-initiated cell populations, and a high-fat diet promotes CD36 in cells with high metastasis potential
.

Interestingly, blocking the neutralizing antibodies of CD36 significantly reduced metastasis
in melanoma and breast cancer.
Regarding the biogenesis of FA, adenosine triphosphate citrate lyase (ACLY), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FASN).
are three key enzymes that catalyze lipid production, and their premetastatic function has been reported
in a variety of cancer settings.
Three phase II clinical trials are currently underway to evaluate the FASN inhibitor TVB-2640 as a single agent for non-small cell lung cancer carrying KRAS mutations ( NCT03808558), or in synergy with paclitaxel and trastuzumab in patients with advanced HER2 breast cancer (NCT03179904), and in combination with patients with first-time recurrent astrocytoma TVB-2640 and bevacizumab (NCT03032484).

The catabolism of lipids is also involved in transfer.

Monoacylglycerol lipase (MAGL), which catalyzes the cleavage of monoacylglycerol (MGs) to free FA, has been shown to accelerate aggressive traits, including metastasis.

The catalytic site of MAGL is irreversibly blocked by JZL184, resulting in impaired metastatic potential of
lung, breast and prostate cancer cells.
These findings highlight the heavy dependence of metastatic cancer cells on specific intracellular lipids, prompting further studies into how reconnected lipid metabolism leads to metastasis
.

Working model of TNFα-activated FOXC2-FA2H axis regulating ceramide metabolic reprogramming in ESCC (Image from Signal Transduction and Targeted Therapy)

Since the lungs are prone to metastases, the authors derived from the ESCC cell lines KYSE30 and KYSE450 (K30P and K450P, respectively Nomenclature) established two groups of cells with high lung metastasis potential - K30LM3 and K450LM2
, respectively.
In genes that are differentially expressed between parental cells (K30P and K450P) and metastatic cells (K30LM3 and K450LM2), fatty acids Increased expression of 2-hydroxylase (FA2H) in metastatic cells
.
FA2H is responsible for adding a hydroxyl group to the C-2 position of the free FAs to generate 2-hydroxy FAs.
Its products are further converted into a branch
of sphingolipids and glycosphingomyides.
FA2H and its catalytic products play a vital role in the epidermis and nervous system under physiological conditions, and mutations in FA2H have been observed to be associated
with spastic hemiplegia and leukodystrophy.

In recent years, evidence that FA2H also plays a role in several cancers has become increasingly clear
.
In the schwannoma cell line D6P2T, FA2H is involved in cAMP-induced cell cycle abort.

Silencing FA2H accelerates the proliferation
of gastric, colorectal, and breast cancer cells.
In addition, the increase of FA2H weakened the resistance of gastric cancer cells to cisplatin treatment, and reduced the intolerability of human cancer cells against the tumor drug PM02734
.
In addition, FA2H is highly expressed in lung adenocarcinoma tissues compared to squamous cell carcinoma and neuroendocrine carcinoma tissues, resulting in the accumulation
of 2-hydroxyHexCers.

FA2H has also been reported to promote in vitro migration
of breast cancer cell lines MDAMB-231 and MCF-7.
These results suggest that FA2H may be a key enzyme controlling cancer cell survival; However, the function and regulatory mechanisms of FA2H in cancer biology, especially in metastasis, need to be further studied
.
Subsequently, the authors investigated how FA2H regulates ESCC metastasis and found that TNFα-activated FOXC2-FA2H axis is a novel facilitator Signal axes
for ESCC cell transfer.

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