■迫切需要有效的治疗方法来解决食管腺癌(EAC)患者惊人的不良生存结果。EAC起源于肠型上皮化生,巴雷特食管,在胃食管反流病和相关炎症的背景下出现的病症。
■这项研究使用了6022个siRNA的可成药基因组小干扰RNA(siRNA)筛选文库,并结合了生物信息学平台,EAC组织的基因组研究,EAC的体细胞变异数据来自EAC的癌症基因组图谱数据,以及病理和功能研究,以定义新的EAC相关,有针对性,免疫因素。
■通过使用药物基因组文库,我们定义了维持EAC细胞生长的基因,其中包括意外的免疫特征。将癌症基因组图谱数据与可药用siRNA靶标整合显示出惊人的一致性和EAC特异性基因扩增事件,该事件与Chr6p21.1共同编码的7个可药用靶标相关。支持EAC细胞生长的免疫途径相关基因的过度表达包括白血病抑制因子,补体成分1,q子成分A链(C1QA),和在骨髓细胞2上表达的触发受体(TREM2),通过基因组和病理研究进一步验证了它们作为共享下游信号通路的靶标。最后,靶向髓样细胞上表达的触发受体2-,C1q-,和白血病抑制因子激活的信号通路(TYROBP-脾酪氨酸激酶和JAK-STAT3)与脾酪氨酸激酶和Janus激活的激酶抑制剂fostatinibR788引发的EAC细胞死亡,生长停滞,并减少NODscidγ小鼠的肿瘤负荷。
■这些数据突出了通过siRNA靶向和表达和体细胞变异的基因组研究共同鉴定的基因子集,特别强调免疫相关因子在支持EAC发展中的贡献,并建议它们适合作为EAC治疗的靶标。
UNASSIGNED: Effective therapeutic approaches are urgently required to tackle the alarmingly poor survival outcomes in esophageal adenocarcinoma (EAC) patients. EAC originates from within the intestinal-type metaplasia, Barrett\'s esophagus, a condition arising on a background of gastroesophageal reflux disease and associated inflammation.
UNASSIGNED: This study used a druggable genome small interfering RNA (siRNA) screening library of 6022 siRNAs in conjunction with bioinformatics platforms, genomic studies of EAC tissues, somatic variation data of EAC from The Cancer Genome Atlas data of EAC, and pathologic and functional studies to define novel EAC-associated, and targetable, immune factors.
UNASSIGNED: By using a druggable genome library we defined genes that sustain EAC cell growth, which included an unexpected immunologic signature. Integrating Cancer Genome Atlas data with druggable siRNA targets showed a striking concordance and an EAC-specific gene amplification event associated with 7 druggable targets co-encoded at Chr6p21.1. Over-representation of immune pathway-associated genes supporting EAC cell growth included leukemia inhibitory factor, complement component 1, q subcomponent A chain (C1QA), and triggering receptor expressed on myeloid cells 2 (TREM2), which were validated further as targets sharing downstream signaling pathways through genomic and pathologic studies. Finally, targeting the triggering receptor expressed on myeloid cells 2-, C1q-, and leukemia inhibitory factor-activated signaling pathways (TYROBP-spleen tyrosine kinase and JAK-STAT3) with spleen tyrosine kinase and Janus-activated kinase inhibitor fostamatinib R788 triggered EAC cell death, growth arrest, and reduced tumor burden in NOD scid gamma mice.
UNASSIGNED: These data highlight a subset of genes co-identified through siRNA targeting and genomic studies of expression and somatic variation, specifically highlighting the contribution that immune-related factors play in support of EAC development and suggesting their suitability as targets in the treatment of EAC.