基础谱系特征的存在意味着高度侵袭性的人类乳腺癌、膀胱癌和胰腺癌。然而，人们对维持这种异常细胞状态的生化机制知之甚少。在这里，我们进行了基于标记的遗传筛选，以寻找维持胰腺导管腺癌（PDAC）基础特性所需的因素。这种方法揭示了 MED12 在这种疾病中是基底细胞状态的强大调节剂。通过生化重建和表观基因组学，我们证明 MED12 通过桥接转录因子 p63（已知的基底谱系主调节因子）与介体复合物来激活谱系特异性增强子元件来实现这一功能。与这一发现一致的是，与经典 PDAC 相比，基底样 PDAC 的生长对 MED12 损失高度敏感。总而言之，我们的全面遗传筛查揭示了维持人类癌症基本特性的生化相互作用，这可以作为肿瘤谱系定向治疗的靶点。

The presence of basal lineage characteristics signifies hyper-aggressive human adenocarcinomas of the breast, bladder, and pancreas. However, the biochemical mechanisms that maintain this aberrant cell state are poorly understood. Here we performed marker-based genetic screens in search of factors needed to maintain basal identity in pancreatic ductal adenocarcinoma (PDAC). This approach revealed MED12 as a powerful regulator of the basal cell state in this disease. Using biochemical reconstitution and epigenomics, we show that MED12 carries out this function by bridging the transcription factor p63, a known master regulator of the basal lineage, with the Mediator complex to activate lineage-specific enhancer elements. Consistent with this finding, the growth of basal-like PDAC is hypersensitive to MED12 loss when compared to classical PDAC. Taken together, our comprehensive genetic screens have revealed a biochemical interaction that sustains basal identity in human cancer, which could serve as a target for tumor lineage-directed therapeutics.