Adipocyte-Induced FABP4 Expression in Ovarian Cancer Cells Promotes Metastasis and Mediates Carboplatin Resistance.
Adipocyte-Induced FABP4 Expression in Ovarian Cancer Cells Promotes Metastasis and Mediates Carboplatin Resistance.
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DOI：
10.1158/0008-5472.can-19-1999
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发表时间：
2020-04-15
期刊：
影响因子：
11.2
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中科院分区：
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脂肪细胞对于卵巢癌（OvCa）细胞归巢到网膜至关重要，但这种相互作用引发的代谢变化尚不清楚。为此，我们对与原代人网膜脂肪细胞共培养的癌细胞进行了无偏的基于质谱的代谢组学和蛋白质组学分析。癌细胞经历了显著的蛋白质代谢组学改变，其典型表现为脂质组的变化以及脂质代谢蛋白的相应上调。FABP 4是一种脂质伴侣蛋白，被鉴定为与脂肪细胞共培养的OvCa细胞中脂质反应的关键调节剂。随后，FABP 4的敲低导致DNA中5-羟甲基胞嘧啶水平增加，与OvCa转移相关的基因特征下调，并降低克隆形成癌细胞存活率。此外，CRISPR介导的FABP 4在高级别浆液性OvCa细胞中的敲除降低了小鼠中的转移性肿瘤负荷。因此，FABP 4的小分子抑制剂（BMS 309403）不仅在同基因原位小鼠模型中显著降低肿瘤负荷，而且在体外和体内增加癌细胞对卡铂的敏感性。总之，这些结果表明，靶向OvCa细胞中的FABP 4可以抑制它们适应和定殖富含脂质的肿瘤微环境的能力，为OvCa转移的特异性代谢靶向提供了机会。
Adipocytes are critical for ovarian cancer (OvCa) cells to home to the omentum, but the metabolic changes initiated by this interaction are unknown. To this end, we carried out unbiased mass spectrometry-based metabolomic and proteomic profiling of cancer cells co-cultured with primary human omental adipocytes. Cancer cells underwent significant proteo-metabolomic alteration(s), typified by changes in the lipidome with corresponding upregulation of lipid metabolism proteins. FABP4, a lipid chaperone protein, was identified as the critical regulator of lipid responses in OvCa cells co-cultured with adipocytes. Subsequently, knockdown of FABP4 resulted in increased 5-hydroxymethylcytosine levels in the DNA, downregulation of gene signatures associated with OvCa metastasis and reduced clonogenic cancer cell survival. In addition, CRISPR-mediated knockout of FABP4 in high-grade serous OvCa cells reduced metastatic tumor burden in mice. Consequently, a small molecule inhibitor of FABP4 (BMS309403) not only significantly reduced tumor burden in a syngeneic orthotopic mouse model but also increased the sensitivity of cancer cells towards carboplatin both in vitro and in vivo. Taken together, these results show that targeting FABP4 in OvCa cells can inhibit their ability to adapt and colonize lipid-rich tumor microenvironments, providing an opportunity for specific metabolic targeting of OvCa metastasis.