为了抵抗谱系依赖性治疗,如雄激素受体抑制,前列腺腔上皮腺癌细胞通常采用干细胞样状态,导致谱系可塑性和表型异质性。去势抵抗性前列腺腺癌可以过渡到神经内分泌,偶尔过渡到苯丙胺,共表达腔和神经内分泌,表型。我们开发了CRPC患者来源的类器官模型,可以保留起源肿瘤的异质性,包括显示一系列腔和神经内分泌表型的苯丙胺模型。为了获得生物学见解并确定异质肿瘤细胞群体中的潜在治疗靶标,我们评估了各种CRPC肿瘤亚群的谱系层次和分子特征.对于所有谱系群体鉴定了转录相似的干/祖细胞。苯丙胺CRPC的谱系追踪表明,异质性起源于不常见的干/祖细胞的不同亚克隆,这些亚克隆主要产生静止的分化的苯丙胺后代。相比之下,腺癌CRPC后代起源于干/祖细胞和自我更新的分化腔细胞。NEPC几乎完全由自我更新的干/祖细胞组成。苯hicrine亚群富含分泌腔,间充质,和以临床进展为特征的恩杂鲁胺治疗持续性特征。最后,用AURKA抑制剂特别耗尽了苯丙胺干/祖细胞亚群,阻止肿瘤生长.这些数据除了证明靶向有分化能力的前列腺干细胞的背景外,还阐明了亚型特异性CRPC的不同干细胞特征。
To resist lineage-dependent therapies such as androgen receptor inhibition, prostate luminal epithelial adenocarcinoma cells often adopt a stem-like state resulting in lineage plasticity and phenotypic heterogeneity. Castrate-resistant prostate adenocarcinoma can transition to neuroendocrine (NE) and occasionally to
amphicrine, co-expressed luminal and NE, phenotypes. We developed castrate-resistant prostate cancer (CRPC) patient-derived organoid models that preserve heterogeneity of the originating tumor, including an
amphicrine model displaying a range of luminal and NE phenotypes. To gain biological insight and to identify potential treatment targets within heterogeneous tumor cell populations, we assessed the lineage hierarchy and molecular characteristics of various CRPC tumor subpopulations. Transcriptionally similar stem/progenitor (St/Pr) cells were identified for all lineage populations. Lineage tracing in amphicrine CRPC showed that heterogeneity originated from distinct subclones of infrequent St/Pr cells that produced mainly quiescent differentiated
amphicrine progeny. By contrast, adenocarcinoma CRPC progeny originated from St/Pr cells and self-renewing differentiated luminal cells. Neuroendocrine prostate cancer (NEPC) was composed almost exclusively of self-renewing St/Pr cells.
Amphicrine subpopulations were enriched for secretory luminal, mesenchymal, and enzalutamide treatment persistent signatures that characterize clinical progression. Finally, the
amphicrine St/Pr subpopulation was specifically depleted with an AURKA inhibitor, which blocked tumor growth. These data illuminate distinct stem cell (SC) characteristics for subtype-specific CRPC in addition to demonstrating a context for targeting differentiation-competent prostate SCs.