Katrii Tetiana, Freywald Tanya, Estrada Malkon G, El Zawily Amr, Toosi Behzad, Vizeacoumar Frederick S, Vizeacoumar Franco J, Freywald Andrew, Leary Scot C
Department of Pathology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
Cancer Research, Division of Oncology, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK, Canada.
Cancer Cell Int. 2025 Jul 19;25(1):272. doi: 10.1186/s12935-025-03909-5.
To investigate whether individually targeting the outer mitochondrial membrane fission receptors FIS1 and MFF rather than the universally essential fission GTPase DRP1 is sufficient to suppress tumor initiating cells (TICs) without causing general mitochondrial dysfunction.
FIS1 or MFF were silenced or knocked out in triple-negative breast cancer (TNBC) cells to investigate their essentiality for maintaining TICs in cell culture and xenograft models. We further investigate the impact of FIS1 deficiency on several functional properties of mitochondria including morphology, membrane potential and ROS production.
We demonstrate that FIS1 absence consistently suppressed TIC populations in cultured TNBC cells, and reduced tumor initiating activity in TNBC xenografts. Remarkably, we found that this phenotypic effect occurred in the absence of significant changes in ROS production, mitochondrial membrane potential and oxidative phosphorylation complex abundance even though FIS1-deficient TICs harbored a more reticular mitochondrial network. Finally, our in silico analyses established that all four DRP1 receptors (FIS1, MFF, MID49 and MID51) are ubiquitously expressed in healthy human tissues, and FIS1 is the most highly expressed DRP1 receptor in mammary gland.
Our data collectively suggest that FIS1 targeting should allow for the suppression of TICs in TNBC tumors without compromising mitochondrial functionality or causing major, systemic toxicity. We believe our findings have the potential to facilitate the development of TIC suppressing therapies for TNBC patients, which is of considerable clinical relevance given that this malignancy has very limited targeted treatment options and is associated with a high mortality rate.
Not applicable.
研究单独靶向线粒体外膜裂变受体FIS1和MFF而非普遍必需的裂变GTP酶DRP1是否足以抑制肿瘤起始细胞（TICs）而不引起一般的线粒体功能障碍。
在三阴性乳腺癌（TNBC）细胞中沉默或敲除FIS1或MFF，以研究它们在细胞培养和异种移植模型中维持TICs的必要性。我们进一步研究了FIS1缺陷对线粒体几种功能特性的影响，包括形态、膜电位和活性氧产生。
我们证明，FIS1缺失持续抑制培养的TNBC细胞中的TIC群体，并降低TNBC异种移植中的肿瘤起始活性。值得注意的是，我们发现即使FIS1缺陷的TICs具有更网状的线粒体网络，这种表型效应也发生在活性氧产生、线粒体膜电位和氧化磷酸化复合物丰度没有显著变化的情况下。最后，我们的计算机分析表明，所有四种DRP1受体（FIS1、MFF、MID49和MID51）在健康人体组织中普遍表达，并且FIS1是乳腺中表达最高的DRP1受体。
我们的数据共同表明，靶向FIS1应能抑制TNBC肿瘤中的TICs，而不损害线粒体功能或引起重大的全身毒性。我们相信我们的发现有可能促进TNBC患者TIC抑制疗法的开发，鉴于这种恶性肿瘤的靶向治疗选择非常有限且死亡率高，这具有相当大的临床相关性。
不适用。
