A NOVEL LINEAGE SPECIFIC METASTASIS PATHWAY IN LUNG CANCER

肺腺癌(LUAD)是组织学上最多样化的肺癌亚型，也是最常见的 转移到中枢神经系统(CNS)。我们的目标是确定LUAD的分子决定因素 血统和组织异质性及其对转移的生物学影响。我们之前确定了 一种新的抑制LUAD细胞侵袭的谱系选择性转录程序，并表明这一点 在高级别LUAD中，通路受到抑制。在这里，我们提供了侵袭性LUAD细胞可以激活的证据 一种神经内分泌样基因信号，一旦肿瘤细胞扩散到大脑，就会进一步诱导这种信号。这 这一现象与具有转移能力的KRAS突变细胞中普遍存在的染色质改变有关。 此外，人类肿瘤中神经内分泌样基因的激活与不同的形态有关。 LUAD亚组有中枢神经系统复发的风险。我们假设：1)LUAD谱系重新编程是由 染色质修饰蛋白，2)组织异质性是一种高级适应能力的衡量标准 LUAD，以及3)神经内分泌谱系的激活特别与他们患上 中枢神经系统复发。许多神经内分泌基因编码具有腺体和神经活性的双重分泌蛋白。 功能。因此，我们还提出4)神经内分泌样基因的一个子集能够使播散性LUAD 细胞建立一个神经源性的小生境，这是脑转移生长所必需的。 我们的机制预测将通过整合表观基因组学、功能基因组学和 实验生物学。这些方法被应用于LUAD的现有模型以及新的模型，这些模型是 通过我们独特的耶鲁肺癌患者同意，在小鼠身上进行工程处理或从患者的活检组织中提取 活组织检查方案。在目标1中，我们进行了功能基因组筛选以命名组蛋白甲基转移酶。 Ash1作为一种新的表观遗传驱动基因，影响谱系可塑性和转移能力。我们会确定舞台 在LUAD进展和转移过程中对Ash1的特殊要求，并确定其机制 它调节转移细胞的转录组。在目标2中，我们确定了神经内分泌/神经活性的双重 FGF9因子在LUAD细胞中表观遗传激活，是脑转移所必需的。我们会从基因上 验证肿瘤细胞来源的FGF9刺激少突胶质祖细胞支持转移的预测 通过旁分泌Sonic Hedgehog信号生长。最后，在目标1和目标2下，我们将利用人类 研究表观基因组改变、神经内分泌标志物表达、 LUAD的组织学异质性和临床转归。 胸部恶性肿瘤是大多数与癌症相关的死亡原因。我们互补的目标提供了一个令人信服的 理解肺规格、神经发生功能、 中枢神经系统复发。最后，我们的建议将对未来的表观遗传学产生重要的见解 治疗方法可用于辅助治疗和/或治疗晚期脑转移瘤。

Lung adenocarcinoma (LUAD) is the most histologically diverse lung cancer subtype and frequently metastasizes to the central nervous system (CNS). Our goal is to identify the molecular determinants of LUAD lineage and histological heterogeneity and their biological consequences for metastasis. We previously identified a novel lineage selective transcriptional program that constrains LUAD cell invasion, and showed that this pathway is suppressed in high grade LUADs. Here, we provide evidence that invasive LUAD cells can activate a neuroendocrine-like gene signature, which is further induced once tumor cells disseminate into the brain. This phenomenon is linked to pervasive chromatin alterations in KRAS mutant cells that are competent for metastasis. Moreover, activation of neuroendocrine-like genes in human tumors correlates with distinct morphological subgroups of LUAD at risk for CNS relapse. We hypothesize that: 1) LUAD lineage reprogramming is driven by chromatin modifying proteins, 2) histological heterogeneity is a measure of the adaptive capacity of high grade LUADs, and 3) the activation of the neuroendocrine lineage in particular correlates with their predisposition for CNS relapse. Many neuroendocrine genes encode for secreted proteins with dual glandular and neuroactive functions. Hence, we also propose that 4) a subset of neuroendocrine-like genes enables disseminated LUAD cells to establish a neurogenic niche that is required for brain metastatic outgrowth. Our mechanistic predictions will be studied by integrating epigenomics, functional genomics, and experimental biology. These methods are applied to existing models of LUAD, as well as new models, which are engineered in mice or derived from biopsies of patients consented through our unique Yale Lung Cancer Patient Biopsy protocol. In Aim 1, we performed a functional genomic screen to nominate the histone methyltransferase ASH1L as a novel epigenetic driver of lineage plasticity and metastatic competence. We will ascertain the stage specific requirement for ASH1L during LUAD progression and metastasis, and identify the mechanism by which it regulates the transcriptome of metastatic cells. In Aim 2, we identified the dual neuroendocrine/neuroactive factor FGF9 as being epigenetically activated in LUAD cells and required for brain metastasis. We will genetically test the prediction that tumor cell derived FGF9 stimulates oligodendrocyte progenitor cells to support metastatic outgrowth via paracrine Sonic Hedgehog signaling. Finally, under both Aims 1 and 2, we will utilize human biospecimens to study the relationship between epigenomic alterations, neuroendocrine marker expression, histological heterogeneity, and clinical outcome in LUAD. Thoracic malignancies account for most cancer-related deaths. Our complementary Aims provide a cogent mechanistic framework to understand the biological link between pulmonary specification, neurogenic functions, and CNS relapse. Finally, our proposal will generate significant insight as to how prospective epigenetic therapies can be harnessed for adjuvant therapy and/or the treatment of late stage brain metastasis.