Departments of Medicine, Oncology, Lady Davis Institute for Medical Research and Segal Cancer Centre, the Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada.
Departments of Medicine, Otolaryngology-Head and Neck Surgery, Lady Davis Institute for Medical Research and Segal Cancer Centre, the Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada.
Oncogene. 2022 May;41(21):2984-2999. doi: 10.1038/s41388-022-02317-7. Epub 2022 Apr 22.
Stemness and chromosomal instability (CIN) are two common contributors to intratumor heterogeneity and therapy relapse in advanced cancer, but their interplays are poorly defined. Here, in anaplastic thyroid cancer (ATC), we show that ALDH+ stem-like cancer cells possess increased CIN-tolerance owing to transcriptional upregulation of the scaffolding protein NEDD9. Thyroid patient tissues and transcriptomic data reveals NEDD9/ALDH1A3 to be co-expressed and co-upregulated in ATC. Compared to bulk ALDH- cells, ALDH+ cells were highly efficient at propagating CIN due to their intrinsic tolerance of both centrosome amplification and micronuclei. ALDH+ cells mitigated the fitness-impairing effects of centrosome amplification by partially inactivating supernumerary centrosomes. Meanwhile, ALDH+ cells also mitigated cell death caused by micronuclei-mediated type 1 interferon secretion by suppressing the expression of the DNA-sensor protein STING. Both mechanisms of CIN-tolerance were lost upon RNAi-mediated NEDD9 silencing. Both in vitro and in vivo, NEDD9-depletion attenuated stemness, CIN, cell/tumor growth, while enhancing paclitaxel effectiveness. Collectively, these findings reveal that ATC progression can involve an ALDH1A3/NEDD9-regulated program linking their stemness to CIN-tolerance that could be leveraged for ATC treatment.
干性和染色体不稳定性（CIN）是导致高级癌症肿瘤内异质性和治疗复发的两个常见因素，但它们之间的相互作用尚未明确界定。在这里，在间变性甲状腺癌（ATC）中，我们表明，ALDH+ 干性样癌细胞由于支架蛋白 NEDD9 的转录上调而具有增加的 CIN 耐受性。甲状腺患者组织和转录组数据表明，NEDD9/ALDH1A3 在 ATC 中共同表达和共同上调。与 bulk ALDH-细胞相比，ALDH+细胞由于其内在的对中心体扩增和微核的耐受性，在增殖 CIN 方面非常高效。ALDH+细胞通过部分失活多余的中心体来减轻中心体扩增的适应性损害。同时，ALDH+细胞还通过抑制 DNA 传感器蛋白 STING 的表达来减轻由微核介导的 1 型干扰素分泌引起的细胞死亡。NEDD9 沉默的 RNAi 介导后，两种 CIN 耐受性机制都丧失了。在体外和体内，NEDD9 耗竭均可减弱干性、CIN、细胞/肿瘤生长，同时增强紫杉醇的有效性。总之，这些发现表明，ATC 进展可能涉及一个 ALDH1A3/NEDD9 调节的程序，将其干性与 CIN 耐受性联系起来，这可能被用于 ATC 治疗。
