Molecular mechanisms underlying lineage plasticity in prostate cancer

项目摘要/摘要 前列腺癌是一种由雄激素引起的疾病，针对 雄激素受体(AR)用于治疗疾病各个阶段的患者。近年来，随着 用较新的药物更早和更有效地靶向AR，即AR非依赖性前列腺癌 已经出现了。我们发现，这与血统可塑性有关，在这种情况下，选择性 治疗压力，肿瘤通过丢失管腔前列腺身份(包括 AR)和获得替代谱系计划，包括神经元/神经内分泌、干状、 和发育途径。在极端情况下，肿瘤可能完全从AR- 阳性前列腺癌(PADC)向AR阴性小细胞/神经内分泌转化 癌症(NEPC)。这种表型改变与临床和分子特征相似。 到小细胞肺癌，表现为快速发展和致命性疾病。我们已经整合了 患者和临床前数据，以识别和分子特征驱动的基因和途径 谱系可塑性包括TP53/RB1的联合丢失、Notch信号的抑制 途径，并上调包括ASCL1和ASCL1在内的谱系决定转录因子(LDTF) INSM1.我们假设Notch信号的丢失会激活LDTF，LDTF与 超级增强剂和染色质调节剂驱动谱系可塑性，AR信号的丢失 依赖性和NEPC进展。为了验证这一假说，我们将调查Noch- INSM1信号在调节LDTF以驱动NEPC进展和治疗耐药性中的作用(目标1)； 广泛描述超级增强子的前景和转录重新编程 管理谱系可塑性(目标2)；并阐明LDTF的转录网络促进 肿瘤从AR驱动的状态向非AR驱动的疾病进化(目标3)。这项提议将 不仅增强了我们对肿瘤进化和细胞特性的理解，而且还将识别新的 靶向谱系可塑性的治疗方法。这些都是改善 前列腺癌患者出现治疗耐药的早期发现、治疗和死亡率。 这一结果也可能与其他癌症类型相关，这些癌症发展为家族可塑性以逃避 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.