Adipocyte-like signature in ovarian cancer minimal residual disease identifies metabolic vulnerabilities of tumor-initiating cells
Adipocyte-like signature in ovarian cancer minimal residual disease identifies metabolic vulnerabilities of tumor-initiating cells
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DOI：
10.1172/jci.insight.147929
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发表时间：
2021-06-08
期刊：
影响因子：
8
通讯作者：
Ahmed, Ahmed Ashour
中科院分区：
文献类型：
--
作者：
Artibani, Mara;Masuda, Kenta;Ahmed, Ahmed Ashour
与肿瘤起始细胞（TIC）类似，微小残留病（MRD）能够重新引发肿瘤并导致复发。然而，实体瘤MRD细胞的分子特征及其存活的驱动因素仍然难以捉摸。在这里，我们对17例卵巢癌患者化疗前后的配对活检组织进行了密集多区域转录组学分析。我们发现，虽然MRD细胞与TIC共享重要的分子特征，但它们也具有脂肪细胞样基因表达特征，并且其中一部分经历了上皮-间充质转化（EMT）。在细胞培养MRD模型中，MRD模拟细胞表现出相同的表型，并依赖于脂肪酸氧化（FAO）的存活和对细胞毒性剂的抗性。这些发现将EMT和FAO确定为根除卵巢癌MRD的有吸引力的靶点，并为进一步测试FAO抑制剂治疗MRD提供了令人信服的理由。
Similar to tumor-initiating cells (TICs), minimal residual disease (MRD) is capable of reinitiating tumors and causing recurrence. However, the molecular characteristics of solid tumor MRD cells and drivers of their survival have remained elusive. Here we performed dense multiregion transcriptomics analysis of paired biopsies from 17 ovarian cancer patients before and after chemotherapy. We reveal that while MRD cells share important molecular signatures with TICs, they are also characterized by an adipocyte-like gene expression signature and a portion of them had undergone epithelial-mesenchymal transition (EMT). In a cell culture MRD model, MRD-mimic cells showed the same phenotype and were dependent on fatty acid oxidation (FAO) for survival and resistance to cytotoxic agents. These findings identify EMT and FAO as attractive targets to eradicate MRD in ovarian cancer and make a compelling case for the further testing of FAO inhibitors in treating MRD.