Hoffman Mariah M, Zylla Jessica S, Bhattacharya Somshuvra, Calar Kristin, Hartman Timothy W, Bhardwaj Ratan D, Miskimins W Keith, de la Puente Pilar, Gnimpieba Etienne Z, Messerli Shanta M
Department of Biomedical Engineering, University of South Dakota, Sioux Falls, SD 57107, USA.
Department of Biomedical Engineering, University of South Dakota, BioSNTR, Sioux Falls, SD 57107, USA.
Cancers (Basel). 2020 Mar 23;12(3):756. doi: 10.3390/cancers12030756.
Central nervous system atypical teratoid/rhabdoid tumors (ATRTs) are rare and aggressive tumors with a very poor prognosis. Current treatments for ATRT include resection of the tumor, followed by systemic chemotherapy and radiation therapy, which have toxic side effects for young children. Gene expression analyses of human ATRTs and normal brain samples indicate that ATRTs have aberrant expression of epigenetic markers including class I histone deacetylases (HDAC's) and lysine demethylase (LSD1). Here, we investigate the effect of a small molecule epigenetic modulator known as Domatinostat (4SC-202), which inhibits both class I HDAC's and Lysine Demethylase (LSD1), on ATRT cell survival and single cell heterogeneity. Our findings suggest that 4SC-202 is both cytotoxic and cytostatic to ATRT in 2D and 3D scaffold cell culture models and may target cancer stem cells. Single-cell RNA sequencing data from ATRT-06 spheroids treated with 4SC-202 have a reduced population of cells overexpressing stem cell-related genes, including . Flow cytometry and immunofluorescence on 3D ATRT-06 scaffold models support these results suggesting that 4SC-202 reduces expression of cancer stem cell markers SOX2, CD133, and FOXM1. Drug-induced changes to the systems biology landscape are also explored by multi-omics enrichment analyses. In summary, our data indicate that 4SC-202 has both cytotoxic and cytostatic effects on ATRT, targets specific cell sub-populations, including those with cancer stem-like features, and is an important potential cancer therapeutic to be investigated in vivo.
中枢神经系统非典型畸胎样/横纹肌样肿瘤（ATRT）是罕见且侵袭性强的肿瘤，预后极差。目前ATRT的治疗方法包括肿瘤切除，随后进行全身化疗和放射治疗，这些对幼儿都有毒副作用。对人类ATRT和正常脑样本的基因表达分析表明，ATRT存在表观遗传标记的异常表达，包括I类组蛋白去乙酰化酶（HDAC）和赖氨酸去甲基化酶（LSD1）。在此，我们研究了一种名为多马司他（4SC-202）的小分子表观遗传调节剂对ATRT细胞存活和单细胞异质性的影响，该调节剂可同时抑制I类HDAC和赖氨酸去甲基化酶（LSD1）。我们的研究结果表明，在二维和三维支架细胞培养模型中，4SC-202对ATRT具有细胞毒性和细胞生长抑制作用，并且可能靶向癌症干细胞。用4SC-202处理的ATRT-06球体的单细胞RNA测序数据显示，过表达干细胞相关基因的细胞群体减少，包括……。对三维ATRT-06支架模型进行的流式细胞术和免疫荧光分析支持了这些结果，表明4SC-202降低了癌症干细胞标志物SOX2、CD133和FOXM1的表达。还通过多组学富集分析探索了药物引起的系统生物学格局变化。总之，我们的数据表明，4SC-202对ATRT具有细胞毒性和细胞生长抑制作用，靶向特定细胞亚群，包括具有癌症干细胞样特征的细胞亚群，是一种重要的潜在癌症治疗药物，有待在体内进行研究。
