Helmholtz-University Group "Cell Plasticity and Epigenetic Remodeling", German Cancer Research Center (DKFZ), Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.
Genome Med. 2024 Jun 17;16(1):83. doi: 10.1186/s13073-024-01357-w.
Somatic copy number alterations are a hallmark of cancer that offer unique opportunities for therapeutic exploitation. Here, we focused on the identification of specific vulnerabilities for tumors harboring chromosome 8p deletions.
We developed and applied an integrative analysis of The Cancer Genome Atlas (TCGA), the Cancer Dependency Map (DepMap), and the Cancer Cell Line Encyclopedia to identify chromosome 8p-specific vulnerabilities. We employ orthogonal gene targeting strategies, both in vitro and in vivo, including short hairpin RNA-mediated gene knockdown and CRISPR/Cas9-mediated gene knockout to validate vulnerabilities.
We identified SLC25A28 (also known as MFRN2), as a specific vulnerability for tumors harboring chromosome 8p deletions. We demonstrate that vulnerability towards MFRN2 loss is dictated by the expression of its paralog, SLC25A37 (also known as MFRN1), which resides on chromosome 8p. In line with their function as mitochondrial iron transporters, MFRN1/2 paralog protein deficiency profoundly impaired mitochondrial respiration, induced global depletion of iron-sulfur cluster proteins, and resulted in DNA-damage and cell death. MFRN2 depletion in MFRN1-deficient tumors led to impaired growth and even tumor eradication in preclinical mouse xenograft experiments, highlighting its therapeutic potential.
Our data reveal MFRN2 as a therapeutic target of chromosome 8p deleted cancers and nominate MFNR1 as the complimentary biomarker for MFRN2-directed therapies.
体细胞拷贝数改变是癌症的一个标志，为治疗利用提供了独特的机会。在这里，我们专注于鉴定携带有 8p 染色体缺失的肿瘤的特定弱点。
我们开发并应用了癌症基因组图谱（TCGA）、癌症依赖性图谱（DepMap）和癌症细胞系百科全书的综合分析，以鉴定 8p 染色体特异性弱点。我们采用正交基因靶向策略，包括体外和体内的短发夹 RNA 介导的基因敲低和 CRISPR/Cas9 介导的基因敲除，以验证弱点。
我们确定 SLC25A28（也称为 MFRN2）是携带有 8p 染色体缺失的肿瘤的特定弱点。我们证明，对 MFRN2 缺失的脆弱性是由其同源物 SLC25A37（也称为 MFRN1）的表达决定的，MFRN1 位于 8p 染色体上。与它们作为线粒体铁转运体的功能一致，MFRN1/2 同源物蛋白缺乏严重损害了线粒体呼吸，导致铁硫簇蛋白的全局耗竭，并导致 DNA 损伤和细胞死亡。在 MFRN1 缺陷型肿瘤中，MFRN2 的耗竭导致在临床前小鼠异种移植实验中生长受损，甚至肿瘤消除，突出了其治疗潜力。
我们的数据揭示了 MFRN2 作为 8p 染色体缺失癌症的治疗靶点，并提名 MFNR1 作为 MFRN2 靶向治疗的互补生物标志物。
