细胞状态转化可控制癌细胞的功能行为，例如上皮→间质转化可赋予癌细胞癌症干细胞样特性、增强致瘤性和耐药性，而间质→上皮转化则可逆转癌细胞的癌症干细胞样特性、致瘤性和耐药性。
2021年10月8日，美国科学促进会《科学》旗下《科学进展》发表新加坡科技研究局、新加坡国立大学、新加坡国立癌症中心、南洋理工大学、新加坡中央医院的研究报告，发现脂肪酸氧化是调节细胞状态可塑性并驱动乳腺癌转移的药物靶点。
该研究通过高通量化学文库筛选，发现维生素A及其类似物类视黄醇是间质→上皮转化的有效促进剂，可抑制基底样乳腺癌或三阴性乳腺癌的致瘤性。脂质代谢重编程可定义细胞状态转化。类视黄醇结合同源核受体可靶向脂质代谢基因，从而将间质细胞状态的β氧化脂肪酸重新转化为上皮细胞状态的脂质储存，抑制该过程关键代谢酶可抑制间质→上皮转化。反之，在动物模型中，抑制脂肪酸氧化可重新引导脂肪酸转化并促进间质→上皮转化，阻止上皮→间质转化引起的乳腺癌转移。
机制分析表明，脂肪酸氧化通过乙酰辅酶A可调节上皮→间质转化基因组蛋白质乙酰化，影响上皮→间质转化的表观遗传控制，从而确定细胞状态。
因此，该研究结果表明，抑制脂肪酸氧化的靶向药物可能有助于阻止乳腺癌转移，尤其对于内分泌治疗和HER2靶向治疗无效的三阴性乳腺癌。
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
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