Tau Steven, Chamberlin Mary D, Yang Huijuan, Marotti Jonathan D, Muskus Patricia C, Roberts Alyssa M, Carmichael Melissa M, Cressey Lauren, Dragnev Christo Philip C, Demidenko Eugene, Hampsch Riley A, Soucy Shannon M, Kolling Fred W, Samkoe Kimberley S, Alvarez James V, Kettenbach Arminja N, Miller Todd W
Department of Molecular and Systems Biology, Dartmouth Geisel School of Medicine, Lebanon, New Hampshire.
Department of Medicine, Dartmouth Geisel School of Medicine, Lebanon, New Hampshire.
Cancer Res. 2025 Mar 14;85(6):1145-1161. doi: 10.1158/0008-5472.CAN-24-1204.
Despite adjuvant treatment with endocrine therapies, estrogen receptor-positive (ER+) breast cancers recur in a significant proportion of patients. Recurrences are attributable to clinically undetectable endocrine-tolerant persister cancer cells that retain tumor-forming potential. Therefore, strategies targeting such persister cells may prevent recurrent disease. Using CRISPR-Cas9 genome-wide knockout screening in ER+ breast cancer cells, we identified a survival mechanism involving metabolic reprogramming with reliance upon mitochondrial respiration in endocrine-tolerant persister cells. Quantitative proteomic profiling showed reduced levels of glycolytic proteins in persisters. Metabolic tracing of glucose revealed an energy-depleted state in persisters, in which oxidative phosphorylation was required to generate ATP. A phase II clinical trial was conducted to evaluate changes in mitochondrial markers in primary ER+/HER2- breast tumors induced by neoadjuvant endocrine therapy (NCT04568616). In an analysis of tumor specimens from 32 patients, tumors exhibiting residual cell proliferation after aromatase inhibitor-induced estrogen deprivation with letrozole showed increased mitochondrial content. Genetic profiling and barcode lineage tracing showed that endocrine-tolerant persistence occurred stochastically without genetic predisposition. Pharmacologic inhibition of mitochondrial complex I suppressed the tumor-forming potential of persisters in mice and synergized with the antiestrogen drug fulvestrant to induce regression of patient-derived xenografts. These findings indicate that mitochondrial metabolism is essential in endocrine-tolerant persister ER+ breast cancer cells and warrant the development of treatment strategies to leverage this vulnerability for treating breast cancer. Significance: Persister cancer cells that survive endocrine therapy exhibit increased energetic dependence upon mitochondria for survival and tumor regrowth potential, indicating that therapies targeting this metabolic dependency could help prevent disease recurrence.
尽管采用内分泌疗法进行辅助治疗，但仍有相当比例的雌激素受体阳性（ER+）乳腺癌患者会复发。复发归因于临床上无法检测到的具有内分泌耐受性的持久性癌细胞，这些细胞保留了形成肿瘤的潜力。因此，针对此类持久性细胞的策略可能预防疾病复发。通过在ER+乳腺癌细胞中进行CRISPR-Cas9全基因组敲除筛选，我们确定了一种生存机制，该机制涉及内分泌耐受性持久性细胞中依赖线粒体呼吸作用的代谢重编程。定量蛋白质组学分析显示，持久性细胞中糖酵解蛋白水平降低。葡萄糖代谢示踪显示，持久性细胞处于能量耗尽状态，其中需要氧化磷酸化来生成ATP。我们开展了一项II期临床试验，以评估新辅助内分泌治疗诱导的原发性ER+/HER2-乳腺肿瘤中线粒体标志物的变化（NCT04568616）。在对32例患者的肿瘤标本进行的分析中，经来曲唑诱导雌激素剥夺后仍有残余细胞增殖的肿瘤显示线粒体含量增加。基因分析和条形码谱系追踪显示，内分泌耐受性持久性的发生是随机的，无遗传易感性。线粒体复合物I的药理学抑制作用可抑制小鼠体内持久性细胞的肿瘤形成潜力，并与抗雌激素药物氟维司群协同作用，诱导患者来源异种移植物消退。这些发现表明，线粒体代谢在内分泌耐受性持久性ER+乳腺癌细胞中至关重要，值得开发治疗策略以利用这一弱点来治疗乳腺癌。意义：在内分泌治疗中存活的持久性癌细胞对线粒体的能量依赖性增加，以实现存活和肿瘤再生潜力，这表明针对这种代谢依赖性的疗法可能有助于预防疾病复发。
