細(xì)胞狀態(tài)轉(zhuǎn)化可控制癌細(xì)胞的功能行為,，例如上皮→間質(zhì)轉(zhuǎn)化可賦予癌細(xì)胞癌癥干細(xì)胞樣特性,、增強(qiáng)致瘤性和耐藥性，而間質(zhì)→上皮轉(zhuǎn)化則可逆轉(zhuǎn)癌細(xì)胞的癌癥干細(xì)胞樣特性,、致瘤性和耐藥性,。

　　2021年10月8日，美國科學(xué)促進(jìn)會《科學(xué)》旗下《科學(xué)進(jìn)展》發(fā)表新加坡科技研究局,、新加坡國立大學(xué),、新加坡國立癌癥中心、南洋理工大學(xué),、新加坡中央醫(yī)院的研究報告,，發(fā)現(xiàn)脂肪酸氧化是調(diào)節(jié)細(xì)胞狀態(tài)可塑性并驅(qū)動乳腺癌轉(zhuǎn)移的藥物靶點(diǎn)。

　　該研究通過高通量化學(xué)文庫篩選,，發(fā)現(xiàn)維生素A及其類似物類視黃醇是間質(zhì)→上皮轉(zhuǎn)化的有效促進(jìn)劑,，可抑制基底樣乳腺癌或三陰性乳腺癌的致瘤性。脂質(zhì)代謝重編程可定義細(xì)胞狀態(tài)轉(zhuǎn)化,。類視黃醇結(jié)合同源核受體可靶向脂質(zhì)代謝基因,，從而將間質(zhì)細(xì)胞狀態(tài)的β氧化脂肪酸重新轉(zhuǎn)化為上皮細(xì)胞狀態(tài)的脂質(zhì)儲存，抑制該過程關(guān)鍵代謝酶可抑制間質(zhì)→上皮轉(zhuǎn)化,。反之,，在動物模型中，抑制脂肪酸氧化可重新引導(dǎo)脂肪酸轉(zhuǎn)化并促進(jìn)間質(zhì)→上皮轉(zhuǎn)化,，阻止上皮→間質(zhì)轉(zhuǎn)化引起的乳腺癌轉(zhuǎn)移,。

　　機(jī)制分析表明，脂肪酸氧化通過乙酰輔酶A可調(diào)節(jié)上皮→間質(zhì)轉(zhuǎn)化基因組蛋白質(zhì)乙?；?，影響上皮→間質(zhì)轉(zhuǎn)化的表觀遺傳控制，從而確定細(xì)胞狀態(tài),。

　　因此,，該研究結(jié)果表明，抑制脂肪酸氧化的靶向藥物可能有助于阻止乳腺癌轉(zhuǎn)移，尤其對于內(nèi)分泌治療和HER2靶向治療無效的三陰性乳腺癌,。

Sci Adv. 2021 Oct 8;7(41):eabh2443.

Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer.

Loo SY, Toh LP, Xie WH, Pathak E, Tan W, Ma S, Lee MY, Shatishwaran S, Yeo JZZ, Yuan J, Ho YY, Peh EKL, Muniandy M, Torta F, Chan J, Tan TJ, Sim Y, Tan V, Tan B, Madhukumar P, Yong WS, Ong KW, Wong CY, Tan PH, Yap YS, Deng LW, Dent R, Foo R, Wenk MR, Lee SC, Ho YS, Lim EH, Tam WL.

Agency for Science, Technology and Research (A*STAR), Singapore, Singapore; National University of Singapore, Singapore, Singapore; National Cancer Centre Singapore, Singapore, Singapore; Nanyang Technological University, Singapore, Singapore; Singapore General Hospital, Singapore, Singapore.

Cell state transitions control the functional behavior of cancer cells. Epithelial-to-mesenchymal transition (EMT) confers cancer stem cell-like properties, enhanced tumorigenicity and drug resistance to tumor cells, while mesenchymal-epithelial transition (MET) reverses these phenotypes. Using high-throughput chemical library screens, retinoids are found to be potent promoters of MET that inhibit tumorigenicity in basal-like breast cancer. Cell state transitions are defined by reprogramming of lipid metabolism. Retinoids bind cognate nuclear receptors, which target lipid metabolism genes, thereby redirecting fatty acids for β-oxidation in the mesenchymal cell state towards lipid storage in the epithelial cell state. Disruptions of key metabolic enzymes mediating this flux inhibit MET. Conversely, perturbations to fatty acid oxidation (FAO) rechannel fatty acid flux and promote a more epithelial cell phenotype, blocking EMT-driven breast cancer metastasis in animal models. FAO impinges on the epigenetic control of EMT through acetyl-CoA-dependent regulation of histone acetylation on EMT genes, thus determining cell states.

PMID: 34613780

DOI: 10.1126/sciadv.abh2443