Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis.
Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis.
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致病性线粒体 DNA 突变抑制黑色素瘤转移。
DOI：
10.1101/2023.09.01.555986
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Mishr
中科院分区：
文献类型：
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作者：
Shelton,SpencerD;House,Sara;Ramesh,Vijayashree;Chen,Zhenkang;Wei,Tao;Wang,Xun;Llamas,ClaireB;Venigalla,SivaSaiKrishna;Menezes,CameronJ;Zhao,Zhiyu;Gill,JenniferG;DeBerardinis,RalphJ;Morrison,SeanJ;Tasdogan,Alpaslan;Mishr
线粒体DNA（mtDNA）突变在癌症中很常见，但它们在癌症进展中的确切作用仍有争议。为了从功能上评估mtDNA变异体对肿瘤生长和转移的影响，我们开发了一种增强的细胞质杂交体（cybrid）生成方案，并建立了具有野生型mtDNA或致病性mtDNA突变的线粒体氧化功能部分或完全丧失的等基因人类黑色素瘤cybrid系。尽管氧化磷酸化功能障碍，但具有致病性mtDNA同质水平的胞质杂交体可靠地建立了肿瘤。然而，这些mtDNA变异破坏了原发性肿瘤的自发转移，并减少了循环肿瘤细胞的丰度。肿瘤细胞的迁移和侵袭减少，表明在mtDNA功能障碍的情况下，进入循环是转移的瓶颈。静脉注射后，致病性mtDNA不抑制器官定植。在异质性胞质杂种肿瘤中，单细胞分析显示在黑色素瘤生长过程中对致病性mtDNA的选择。总的来说，这些发现实验证明，功能性mtDNA在黑色素瘤生长过程中是有利的，并支持转移进入血液。
Mitochondrial DNA (mtDNA) mutations are frequent in cancer, yet their precise role in cancer progression remains debated. To functionally evaluate the impact of mtDNA variants on tumor growth and metastasis, we developed an enhanced cytoplasmic hybrid (cybrid) generation protocol and established isogenic human melanoma cybrid lines with wild-type mtDNA or pathogenic mtDNA mutations with partial or complete loss of mitochondrial oxidative function. Cybrids with homoplasmic levels of pathogenic mtDNA reliably established tumors despite dysfunctional oxidative phosphorylation. However, these mtDNA variants disrupted spontaneous metastasis from primary tumors and reduced the abundance of circulating tumor cells. Migration and invasion of tumor cells were reduced, indicating that entry into circulation is a bottleneck for metastasis amid mtDNA dysfunction. Pathogenic mtDNA did not inhibit organ colonization following intravenous injection. In heteroplasmic cybrid tumors, single-cell analyses revealed selection against pathogenic mtDNA during melanoma growth. Collectively, these findings experimentally demonstrate that functional mtDNA is favored during melanoma growth and supports metastatic entry into the blood.