Mitochondrial structure and function adaptation in residual triple negative breast cancer cells surviving chemotherapy treatment.
Mitochondrial structure and function adaptation in residual triple negative breast cancer cells surviving chemotherapy treatment.
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DOI：
10.1038/s41388-023-02596-8
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发表时间：
2023-03
期刊：
影响因子：
8
通讯作者：
Echeverria, Gloria V.
中科院分区：
文献类型：
--
作者：
Baek, Mokryun L.;Lee, Junegoo;Pendleton, Katherine E.;Berner, Mariah J.;Goff, Emily B.;Tan, Lin;Martinez, Sara A.;Mahmud, Iqbal;Wang, Tao;Meyer, Matthew D.;Lim, Bora;Barrish, James P.;Porter, Weston;Lorenzi, Philip L.;Echeverria, Gloria V.
用于三阴性乳腺癌（TNBC）的新辅助化疗（NACT）根除了大约45%的患者肿瘤。不幸的是，有大量残余肿瘤负担的TNBC患者无转移和总生存率较差。我们之前证明线粒体氧化磷酸化（OXPHOS）升高，是NACT存活的残余TNBC细胞的独特治疗依赖性。我们试图研究这种对线粒体代谢增强依赖的机制。线粒体是形态上可塑的细胞器，在裂变和融合之间循环，以维持线粒体的完整性和代谢稳态。线粒体结构对代谢输出的功能影响高度依赖于环境。几种化疗药物通常用于TNBC患者的新辅助治疗。通过比较常规化疗对线粒体的影响，我们发现dna损伤剂增加了线粒体伸长、线粒体含量、通过TCA循环的葡萄糖通量和OXPHOS，而紫杉烷反而降低了线粒体伸长和OXPHOS。dna损伤化疗的线粒体效应依赖于线粒体内膜融合蛋白optic atrophy 1 （OPA1）。此外，我们观察到原位患者来源的残余TNBC异种移植（PDX）模型中OXPHOS， OPA1蛋白水平和线粒体伸长升高。线粒体融合和分裂的药理学或遗传破坏分别导致OXPHOS减少或增加，这表明TNBC细胞中较长的线粒体有利于OXPHOS。通过TNBC细胞系和体内残余TNBC的PDX模型，我们发现依次进行dna损伤化疗，从而诱导线粒体融合和OXPHOS，然后使用特异性抑制剂MYLS22 (OPA1)，能够抑制线粒体融合和OXPHOS，并显著抑制残余肿瘤细胞的再生。我们的数据表明TNBC线粒体可以通过opa1介导的线粒体融合来优化OXPHOS。这些发现可能为克服化疗耐药TNBC的线粒体适应性提供了机会。
Neoadjuvant chemotherapy (NACT) used for triple negative breast cancer (TNBC) eradicates tumors in approximately 45% of patients. Unfortunately, TNBC patients with substantial residual cancer burden have poor metastasis free and overall survival rates. We previously demonstrated mitochondrial oxidative phosphorylation (OXPHOS) was elevated and was a unique therapeutic dependency of residual TNBC cells surviving NACT. We sought to investigate the mechanism underlying this enhanced reliance on mitochondrial metabolism. Mitochondria are morphologically plastic organelles that cycle between fission and fusion to maintain mitochondrial integrity and metabolic homeostasis. The functional impact of mitochondrial structure on metabolic output is highly context dependent. Several chemotherapy agents are conventionally used for neoadjuvant treatment of TNBC patients. Upon comparing mitochondrial effects of conventional chemotherapies, we found that DNA-damaging agents increased mitochondrial elongation, mitochondrial content, flux of glucose through the TCA cycle, and OXPHOS, whereas taxanes instead decreased mitochondrial elongation and OXPHOS. The mitochondrial effects of DNA-damaging chemotherapies were dependent on the mitochondrial inner membrane fusion protein optic atrophy 1 (OPA1). Further, we observed heightened OXPHOS, OPA1 protein levels, and mitochondrial elongation in an orthotopic patient-derived xenograft (PDX) model of residual TNBC. Pharmacologic or genetic disruption of mitochondrial fusion and fission resulted in decreased or increased OXPHOS, respectively, revealing longer mitochondria favor oxphos in TNBC cells. Using TNBC cell lines and an in vivo PDX model of residual TNBC, we found that sequential treatment with DNA-damaging chemotherapy, thus inducing mitochondrial fusion and OXPHOS, followed by MYLS22, a specific inhibitor of OPA1, was able to suppress mitochondrial fusion and OXPHOS and significantly inhibited regrowth of residual tumor cells. Our data suggest that TNBC mitochondria can optimize OXPHOS through OPA1-mediated mitochondrial fusion. These findings may provide an opportunity to overcome mitochondrial adaptations of chemoresistant TNBC.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
16.6
作者：
Anderson GR;Wardell SE;Cakir M;Yip C;Ahn YR;Ali M;Yllanes AP;Chao CA;McDonnell DP;Wood KC
通讯作者：
Wood KC
影响因子：
9
作者：
Chen L;Zhang J;Lyu Z;Chen Y;Ji X;Cao H;Jin M;Zhu J;Yang J;Ling R;Xing J;Ren T;Lyu Y
通讯作者：
Lyu Y
影响因子：
46.9
作者：
Cui L;Gouw AM;LaGory EL;Guo S;Attarwala N;Tang Y;Qi J;Chen YS;Gao Z;Casey KM;Bazhin AA;Chen M;Hu L;Xie J;Fang M;Zhang C;Zhu Q;Wang Z;Giaccia AJ;Gambhir SS;Zhu W;Felsher DW;Pegram MD;Goun EA;Le A;Rao J
通讯作者：
Rao J
影响因子：
2.7
作者：
Decker CW;Garcia J;Gatchalian K;Arceneaux D;Choi C;Han D;Hernandez JB
通讯作者：
Hernandez JB