癌细胞可塑性是肿瘤细胞在微环境压力下改变其身份并获得新生物学特性的能力。在前列腺癌（PCa）中，谱系可塑性常常导致治疗抵抗和向神经内分泌（NE）谱系的转分化。然而，识别具有谱系可塑性相关状态的癌细胞仍然具有挑战性。基于 13 个多中心人类 PCa 批量转录组队列（样本 = 3314）和来自 PCa 实验模型的 9 个批量转录组数据集，我们建立了一个集成的谱系可塑性相关状态的癌细胞。基因签名，称为 LPSig。利用该基因特征，应用 AUCell 富集分析从我们组装的综合单细胞 RNA 测序 (scRNA-seq) 元图谱中识别出具有高谱系可塑性的细胞群，该图谱由 10 个公共人类 PCa scRNA-seq 组成数据集（样本 = 93，单元格 = 222,529）。此外，还采用了人类 PCa 的额外 scRNA-seq 数据集、人类 PCa 组织的多重免疫组织化学染色、体外和体内功能实验以及 qPCR 和蛋白质印迹分析来验证我们的发现。我们发现 LPSig 可以精细地捕获整个 PCa 进展过程中肿瘤谱系可塑性的动态变化，准确估计谱系可塑性的状态。基于 LPSig，我们从本研究组装的人类 PCa scRNA-seq 元图谱中鉴定出了先前未定义的少数谱系可塑性相关 PCa 细胞 (LPC) 群体。此外，深入剖析揭示了 LPC 在转分化、肿瘤复发和 PCa 进展期间患者生存率低下的关键作用。此外，我们确定 HMMR 作为 LPC 的代表性细胞表面标记物，并使用额外的 scRNA-seq 数据集和多重免疫组织化学对其进行了验证。此外，HMMR 在转录上受到雄激素受体 (AR) 的抑制，并且是侵袭性腺癌特征和 NE 表型所必需的。我们的研究发现了一个新的谱系可塑性相关细胞群，具有低 AR 活性、干性样特征和升高的 HMMR表达，可能会导致 PCa 预后不良。这项工作得到了国家重点研发项目的支持

Cancer cell plasticity is the ability of neoplastic cells to alter their identity and acquire new biological properties under microenvironmental pressures. In prostate cancer (PCa), lineage plasticity often results in therapy resistance and trans-differentiation to neuroendocrine (NE) lineage. However, identifying the cancer cells harboring lineage plasticity-related status remains challenging.Based on 13 multi-center human PCa bulk transcriptomic cohorts (samples = 3314) and 9 bulk transcriptomic datasets derived from PCa experimental models, we established an integrated lineage plasticity-related gene signature, termed LPSig. Leveraging this gene signature, AUCell enrichment analysis was applied to identify the cell population with high lineage plasticity from a comprehensive single-cell RNA-sequencing (scRNA-seq) meta-atlas assembled by us, which consisted of 10 public human PCa scRNA-seq datasets (samples = 93, cells = 222,529). Moreover, additional scRNA-seq dataset of human PCa, multiplex immunohistochemistry staining for human PCa tissues, in vitro and in vivo functional experiments, as well as qPCR and Western blot analyses were employed to validate our findings.We found that LPSig could finely capture the dynamics of tumor lineage plasticity throughout the progression of PCa, accurately estimating the status of lineage plasticity. Based on LPSig, we identified a previously undefined minority population of lineage plasticity-related PCa cells (LPCs) from the human PCa scRNA-seq meta-atlas assembled by this study. Furthermore, in-depth dissection revealed pivotal roles of LPCs in trans-differentiation, tumor recurrence, and poor patient survival during PCa progression. Furthermore, we identified HMMR as a representative cell surface marker for LPCs, which was validated using additional scRNA-seq datasets and multiplexed immunohistochemistry. Moreover, HMMR was transcriptionally inhibited by androgen receptor (AR), and was required for the aggressive adenocarcinoma features and NE phenotype.Our study uncovers a novel population of lineage plasticity-related cells with low AR activity, stemness-like traits, and elevated HMMR expression, that may facilitate poor prognosis in PCa.This work was supported by National Key R&D Program of China (2022YFA0807000), National Natural Science Foundation of China (82160584), Advanced Prostate Cancer Diagnosis and Treatment Technology Innovation Team of Kunming Medical University (CXTD202216), and Reserve Talents of Young and Middle-aged Academic Leaders in Yunnan Province (202105AC160013).Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.