Human tumors are characterized by extensive intratumoral transcriptional variability within the cancer cell and stromal compartments. This variation drives phenotypic heterogeneity, producing cell states with differential pro- and anti-tumorigenic properties. While bulk RNA sequencing cannot achieve cell-type-specific transcriptional granularity, single-cell sequencing has permitted an unprecedented view of these cell states. Despite this knowledge, we lack an understanding of the mechanistic drivers of this transcriptional and phenotypic heterogeneity. 3′ untranslated region alternative polyadenylation (3′ UTR-APA) drives gene expression alterations through regulation of 3′ UTR length. These 3′ UTR alterations modulate mRNA stability, protein expression and protein localization, resulting in cellular phenotypes including differentiation, cell proliferation, and migration. Therefore, we sought to determine whether 3′ UTR-APA events could characterize phenotypic heterogeneity of tumor cell states. Here, we analyze the largest single-cell human pancreatic ductal adenocarcinoma (PDAC) dataset and resolve 3′ UTR-APA patterns across PDAC cell states. We find that increased proximal 3′ UTR-APA is associated with PDAC progression and characterizes a metastatic ductal epithelial subpopulation and an inflammatory fibroblast population. Furthermore, we find significant 3′ UTR shortening events in cell-state-specific marker genes associated with increased expression. Therefore, we propose that 3′ UTR-APA drives phenotypic heterogeneity in cancer.
人类肿瘤的特征在于癌细胞和基质区室内存在广泛的瘤内转录异质性。这种变异驱动表型异质性，产生具有不同促瘤和抗瘤特性的细胞状态。虽然批量RNA测序无法达到细胞类型特异性的转录分辨率，但单细胞测序技术为这些细胞状态提供了前所未有的观察视角。尽管已有这些认知，我们仍缺乏对这种转录和表型异质性机制驱动因素的理解。3′非翻译区选择性多聚腺苷酸化通过调控3′UTR长度驱动基因表达改变。这些3′UTR变化调节mRNA稳定性、蛋白质表达和蛋白质定位，从而导致包括分化、细胞增殖和迁移在内的细胞表型。因此，我们试图探究3′UTR-APA事件是否能够表征肿瘤细胞状态的表型异质性。本研究分析了最大规模的人类胰腺导管腺癌单细胞数据集，解析了不同PDAC细胞状态间的3′UTR-APA模式。我们发现近端3′UTR-APA的增加与PDAC进展相关，并表征了转移性导管上皮亚群和炎性成纤维细胞群。此外，我们在细胞状态特异性标记基因中发现了显著的3′UTR缩短事件，这些事件与基因表达增加相关。因此，我们提出3′UTR-APA驱动癌症表型异质性的理论。
肿瘤(癌症)患者之家