使用放射性配体和抗体疗法靶向细胞表面分子在癌症治疗中取得了相当大的成功。然而，目前尚不清楚假定的谱系标记物，特别是细胞表面分子的表达在谱系可塑性过程中如何变化，其中肿瘤细胞改变其身份并获得新的致癌特性。谱系可塑性的一个显着例子是前列腺腺癌（PRAD）向神经内分泌前列腺癌（NEPC）的转变，这是一种不断增长的耐药机制，导致对雄激素阻断的反应性丧失，并预示着患者生存的惨淡。为了了解谱系标记在前列腺癌谱系可塑性进化过程中的变化，我们对 21 个人类前列腺肿瘤活检组织和两个基因工程小鼠模型进行了单细胞分析，并对 131 个肿瘤样本进行了组织微阵列分析。我们不仅观察到去势抵抗性 PRAD 和 NEPC 的表型异质性程度高于之前的预期，而且还发现治疗靶向分子（即 PSMA、STEAP1、STEAP2、TROP2、CEACAM5 和 DLL3）的表达在一个子集中存在差异。基因调控网络（GRN）。我们还注意到，NEPC 和小细胞肺癌亚型共享一组 GRN，这表明可以在跨肿瘤类型的治疗中利用保守的生物学途径。虽然这种极端水平的转录异质性，特别是在细胞表面标志物表达方面，可能会降低对当前和未来抗原导向疗法的临床反应的持久性，但其描述可能会为临床试验中的患者选择产生特征，可能跨越不同的癌症类型。

Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)-a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single-cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate-resistant PRAD and NEPC than previously anticipated but also found that the expression of molecules targeted therapeutically, namely PSMA, STEAP1, STEAP2, TROP2, CEACAM5, and DLL3, varied within a subset of gene-regulatory networks (GRNs). We also noted that NEPC and small cell lung cancer subtypes shared a set of GRNs, indicative of conserved biologic pathways that may be exploited therapeutically across tumor types. While this extreme level of transcriptional heterogeneity, particularly in cell surface marker expression, may mitigate the durability of clinical responses to current and future antigen-directed therapies, its delineation may yield signatures for patient selection in clinical trials, potentially across distinct cancer types.