Exploiting mitochondrial heteroplasmy for cancer chemotherapy

项目摘要 标题：利用线粒体异质性进行癌症化疗 大约三分之一的患者癌症是异质性的--也就是说，单个细胞含有混合的基因 不同的线粒体基因组--其中很大一部分带有严重的功能丧失突变 影响呼吸所必需的基因。这些突变似乎是乘客而不是司机 肿瘤发生，但我们的实验室最近发现，它们可以使癌细胞株和异种移植更多 易受用于治疗2型糖尿病的线粒体抑制剂双胍类药物的影响。因为异质性是 在正常组织中相对罕见，这些发现表明线粒体抑制剂可能有治疗作用 治疗异质性癌症的窗口，但具体地说，这种异质性可能是何时和如何 被开发用于治疗的人仍然知之甚少。此外，我们的工作表明，异质性是一种 可逆性遗传缺陷，因为异质细胞通常仍含有野生型的 线粒体基因组，而这种部分逆转是耐药的一条途径。这一减少 异质性不是一个简单的突变过程，其机制尚不清楚。拟议中的工作 旨在通过对异质性如何影响的系统研究来填补当前知识的这两个空白 对各种相关抑制剂的敏感性以及这些抑制剂如何推动异质性的变化 导致抗药性。

Project Summary Title: Exploiting mitochondrial heteroplasmy for cancer chemotherapy Roughly a third of patient cancers are heteroplasmic -- that is, individual cells harbor a mixture of genetically distinct mitochondrial genomes -- and a substantial fraction of these bear severe loss-of-function mutations affecting genes necessary for respiration. These mutations appear to be passengers rather than drivers of tumorgenesis, but our lab recently discovered that they can render cancer cell lines and xenografts more vulnerable to biguanides, mitochondrial inhibitors used to treat type 2 diabetes. Since heteroplasmy is relatively rare in normal tissues, these findings suggest that mitochondrial inhibitors may have a therapeutic window for treating heteroplasmic cancers, but specifically when and how this heteroplasmy may be exploited for treatment remains poorly understood. Additionally, our work showed that heteroplasmy is a reversible genetic defect, since heteroplasmic cells generally still contain wild-type copies of the mitochondrial genome, and that partial reversion is a route to drug resistance. This reduction of heteroplasmy is not a simple mutational processes, and its mechanisms are unknown. The proposed work aims to fill both of these gaps in current knowledge with a systematic study of how heteroplasmy affects susceptibility to a variety of relevant inhibitors and how these inhibitors may drive changes in heteroplasmy leading to drug resistance.