PO.MCB07.02 · 分子与细胞生物学
定义并靶向干细胞样前列腺癌中谱系可塑性的驱动因素
Defining and targeting drivers of lineage plasticity in stem cell-like prostate cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
前列腺癌的生长依赖于雄激素受体（AR）信号，这也是雄激素剥夺（去势）疗法在早期阶段有效的原因。然而，许多肿瘤最终进展为一种致命形式，称为去势抵抗性前列腺癌（CRPC）。一部分CRPC肿瘤通过获得谱系可塑性绕过对AR信号的依赖，其中前列腺癌细胞通过表观遗传重编程转分化为其他细胞状态。神经内分泌（NE）前列腺癌是一种著名的谱系可塑性表型。然而，大多数AR非依赖性肿瘤并不表现出NE特征，被定义为AR阴性/NE阴性或“双阴性前列腺癌”（DNPC）。在与Weill Cornell Medicine的Ekta Khurana博士计算基因组学实验室的合作中，我们最近将CRPC分为四种表观遗传亚型，包括公认的1）AR和2）NE，以及新的DNPC亚组3）WNT和4）干细胞样（SCL）（PMID: 35617398）。我们聚焦于SCL亚型，因为它是CRPC患者中第二常见的组，且缺乏治疗靶点。使用功能基因组学方法，我们发现YAP/TAZ/TEAD与FOSL1协同作用以驱动SCL谱系和SCL模型的生长。因此，我们假设对YAP/TAZ/TEAD/FOSL1转录程序的高度依赖代表了CRPC-SCL中的治疗弱点。为验证这一点，我们将CRPC模型暴露于TEAD抑制剂，发现与非SCL细胞相比，SCL细胞在体外的生长受到强烈抑制。为评估TEAD抑制剂是否具有靶点特异性，我们在SCL模型中进行了转录组分析，观察到YAP/TAZ基因特征以及FOSL1表达下调，这与YAP/TAZ双敲低的效应表型一致。为定义这些因子在TEAD抑制后的顺式作用组，我们进行了ChIP-seq，观察到共有位点处共占据减少，提示小分子化合物破坏了YAP/TAZ/TEAD/FOSL1转录环路。为确定这些表型是否在体内重现，我们将用TEAD抑制剂治疗携带CRPC-SCL异种移植物的小鼠，以评估生长反应，并使用单核多组学（Multiome，ATAC+RNA）评估表观遗传和转录反应。这些研究将确定TEAD的小分子抑制是否是治疗CRPC-SCL的有前景的策略，并允许对细胞状态转变进行高分辨率分析，重点关注SCL特异性特征的丧失以及作为适应性耐药机制的AR/NE程序的潜在出现。
查看英文原文 English abstract
Prostate cancer depends on androgen receptor (AR) signaling for growth, which is why androgen deprivation (castration) therapy is effective at early stages. However, many tumors eventually progress to a lethal form known as castration-resistant prostate cancer (CRPC). A subset of CRPC tumors bypass dependency on AR signaling by acquiring lineage plasticity, where prostate cancer cells transdifferentiate into alternate cellular states through epigenetic reprogramming. Neuroendocrine (NE) prostate cancer represents one well-known lineage plasticity phenotype. Nevertheless, most AR-independent tumors do not exhibit NE features and are defined as AR-negative/NE-negative or “double-negative prostate cancer” (DNPC). In a collaboration with Dr. Ekta Khurana's computational genomics lab at Weill Cornell Medicine, we recently classified CRPC into four epigenetic subtypes, including the well-established 1) AR and 2) NE, as well as the novel DNPC subgroups 3) WNT and 4) stem cell-like (SCL) (PMID: 35617398). We focused on the SCL subtype as it is the second most common group in CRPC patients and lacks therapeutic targets. Using functional genomic approaches, we found that YAP/TAZ/TEAD cooperates with FOSL1 to drive the SCL lineage and growth of SCL models. We therefore hypothesize that the heightened dependency on the YAP/TAZ/TEAD/FOSL1 transcriptional program represents a therapeutic vulnerability in CRPC-SCL. To test this, we exposed CRPC models to TEAD inhibitors and found robust growth suppression in SCL cells compared to non-SCL cells in vitro. To evaluate whether the TEAD inhibitors are on-target, we performed transcriptomic profiling in SCL models and observed downregulation of YAP/TAZ gene signature as well as FOSL1 expression, which phenocopies the effects of YAP/TAZ double knockdown. To define the cistromes of these factors upon TEAD inhibition, we performed ChIP-seq and observed reduced co-occupancy at consensus sites, suggesting the disruption of the YAP/TAZ/TEAD/FOSL1 transcriptional circuit by the small molecule compound. To determine whether these phenotypes are recapitulated in vivo , we will treat mice harboring CRPC-SCL xenografts with TEAD inhibitors to assess growth response and evaluate epigenetic and transcriptional response using single-nucleus Multiome (ATAC+RNA). These studies will establish whether small molecule inhibition of TEAD is a promising strategy for the treatment of CRPC-SCL and allow high-resolution analysis of cell state transitions, with a focus on loss of SCL-specific signatures and potential emergence of AR/NE programs as adaptive resistance mechanisms.
利益披露 Disclosure
C. K. Wong, None..
D. Li, None.