Molecular mechanisms underlying lineage plasticity in prostate cancer

项目总结/摘要 前列腺癌作为雄激素驱动的疾病而出现，并且靶向前列腺癌的全身性治疗是有效的。 雄激素受体（AR）用于治疗处于疾病所有阶段的患者。近年来随着 用新药更早更有效地靶向AR， 出现了我们发现这与谱系可塑性有关， 在治疗压力下，肿瘤通过失去管腔前列腺特性（包括 AR）和获得替代谱系程序，包括神经元/神经内分泌，干细胞样， 和发展途径。在极端情况下，肿瘤可能完全从AR- 阳性前列腺腺癌（PADC）向AR阴性小细胞/神经内分泌 癌（NEPC）。这种表型变化与临床和分子特征相似 到小细胞肺癌，表现为快速进展和致命的疾病。我们整合 患者和临床前数据，以确定和分子表征基因和途径， 谱系可塑性，包括TP 53/RB 1的联合缺失，Notch信号传导的抑制， 途径，以及包括ASCL 1和 INSM 1.我们假设Notch信号转导的缺失激活了LDTF，LDTF与Notch信号转导协同作用。 超级增强子和染色质调节子驱动谱系可塑性，AR信号传导的丧失 依赖和NEPC进展。为了验证这一假设，我们将研究NOTCH的作用- INSM 1信号转导在调节LDTF中驱动NEPC进展和治疗抗性（Aim 1）; 广泛表征超级增强子景观和转录重编程， 控制谱系可塑性（目的2）;并阐明LDTF的转录网络，促进 肿瘤从AR驱动的状态向非AR驱动的疾病演变（Aim 3）。这项建议会 不仅增强了我们对肿瘤演变和细胞特性的理解， 针对谱系可塑性的治疗方法。这些都是改善 前列腺癌患者的早期发现、治疗和死亡率。 结果也可能与其他癌症类型有关，这些癌症发展出谱系可塑性，以逃避 有效的靶向治疗，如肺癌、黑色素瘤和乳腺癌。

Project Summary/Abstract Prostate cancer arises as an androgen driven disease, and systemic therapies that target the androgen receptor (AR) are used to treat patients at all stages of the disease. In recent years, with the earlier and more potent targeting of the AR with newer drugs, AR-independent prostate cancer has emerged. We have found that this is associated with lineage plasticity in which upon selective therapeutic pressure, tumors evade AR-therapy through loss of luminal prostate identity (including AR) and the acquisition of alternative lineage programs including neuronal/neuroendocrine, stem-like, and developmental pathways. In extreme cases, tumors may completely transition from an AR- positive prostate adenocarcinoma (PADC) toward an AR-negative small cell/neuroendocrine carcinoma (NEPC). This phenotypic change is associated with clinical and molecular features similar to small cell lung cancer, manifest by rapid progression and lethal disease. We have integrated patient and preclinical data to identify and molecularly characterize genes and pathways that drive lineage plasticity including the combined loss of TP53/RB1, suppression of the Notch signaling pathway, and up-regulation of lineage-determining transcription factors (LDTFs) including ASCL1 and INSM1. We hypothesize that loss of Notch signaling activates LDTFs, which act coordinately with super-enhancers and chromatin regulators to drive lineage plasticity, loss of AR signaling dependence, and NEPC progression. To test this hypothesis, we will investigate the role of NOTCH- INSM1 signaling in regulating LDTFs to drive NEPC progression and treatment resistance (Aim 1); extensively characterize the super-enhancer landscape and transcriptional reprogramming that governs lineage plasticity (Aim 2); and elucidate the transcriptional network of LDTFs that promote tumor evolution from an AR-driven state towards non-AR driven disease (Aim 3). This proposal will not only enhance our understanding of tumor evolution and cell identity, but will also identify new therapeutic approaches to target lineage plasticity. These are critical steps towards improving the early detection, treatment, and mortality of prostate cancer patients developing treatment resistance. Results may also have relevance in other cancer types that develop lineage plasticity to evade effective targeted therapies, such as lung cancer, melanoma, and breast cancer.