Bimodal EGFR signaling in glioblastoma

摘要 胶质母细胞瘤(GBM)是成人最常见的原发性脑癌。EGFR在大多数细胞中都有表达 基底膜和异常的EGFR信号是恶性表型的主要驱动因素。尽管EGFR是 被认为是GBM的主要癌基因，TCGA分析表明在EGFR扩增的GBM中，EGFR配体 对肿瘤有抑制作用。我们的初步数据还表明，配体激活的EGFR具有肿瘤抑制作用。 配体激活的EGFR的肿瘤抑制作用产生了意想不到的侵袭抑制。 我们认为，构成和配体依赖的EGFR野生型信号触发不同的信号转导 小路。因此，结构性的EGFR信号促进侵袭，而配体激活的EGFR信号转而 关于核扩散和关闭入侵。我们阐明了EGFR调节侵袭性和 确定BIN3，一种已知影响细胞骨架的蛋白质，是GBM入侵的关键抑制因子。我们也 配体激活的EGFR介导的胶质瘤细胞的作用机制及其生物学意义 扩散。我们研究了增殖和侵袭对肿瘤大小和预后的相对贡献。 GBM。更好地了解推动GBM侵袭的机制是改进治疗的关键。 此外，我们确定tofacitinib是一种可以通过以下方式激活EGFR抑瘤功能的药物 增加EGFR配体，上调BIN3，抑制GBM侵袭。托法替尼是一种临床可用的 以及FDA批准的药物。我们的模型适用于表达EGFR野生型或突变体的GBM EGFRvIII.在特定的目标1：我们阐明了RTK反式激活在驱动侵袭或增殖中的作用。 我们验证了这样的假设，即结构性的EGFR信号促进EGFR的侵袭性，而配体诱导 EGFR信号会阻止它。结构性EGFR信号导致Met激活，导致Met升高 侵犯性。我们还发现了一条TAB1-TAK1-NF-B通路，驱动GBM的侵袭。配基激活 EGFR信号转导导致Axl活化和增殖，降低GBM侵袭力。具体目标2： 我们揭示了EGFR用来抑制GBM细胞侵袭性的机制。我们检验了这一假设 BIN3是侵袭的主要负性调节因子。配体诱导的EGFR活性上调BIN3和 抑制入侵。我们检测了BIN3、BIN3伙伴、EGFR和其他RTK的表达模式 GBM中的网络。在特定的目标3中，我们研究了结构性与配体诱导的生物学效应。 EGFR-RTK-BIN3信号转导在小鼠原位肾小球系膜侵袭中的作用 特异性抑制缺乏配体的GBM侵袭的治疗。。

Abstract Glioblastoma (GBM) is the most common primary brain cancer in adults. EGFR is expressed in the majority of GBMs and aberrant EGFR signaling is a major driver of the malignant phenotype. Although the EGFR is considered a prime oncogene in GBM, TCGA analysis indicates that in EGFR amplified GBMs, EGFR ligands are tumor suppressive. Our preliminary data also suggest that ligand-activated EGFR is tumor suppressive. The tumor suppressive effects of ligand-activated EGFR result form an unexpected suppression of invasion. We propose that constitutive and ligand-dependent EGFR wild type signaling triggers distinct signaling pathways. Thus, constitutive EGFR signaling promotes invasion while ligand-activated EGFR signaling turns on proliferation and turns off invasion. We elucidate mechanisms underlying EGFR regulation of invasion and identify BIN3, a protein known to influence the cytoskeleton, as a key suppressor of GBM invasion. We also identify the mechanisms and biological significance of ligand-activated EGFR mediated glioma cell proliferation. We examine the relative contribution of proliferation and invasion to tumor size and prognosis in GBM. An improved understanding of mechanisms that drive GBM invasion is critical to improved treatment. Furthermore, we identify tofacitinib as a drug that can activate the tumor suppressor function of EGFR by increasing EGFR ligand, upregulating BIN3 and suppressing GBM invasion. Tofacitinib is a clinically available and FDA approved drug. Our model holds true for GBMs that express EGFR wild type or the mutant EGFRvIII. In Specific Aim 1: We elucidate the role of RTK transactivation in driving invasion or proliferation. We test the hypothesis that constitutive EGFR signaling promotes EGFR invasiveness whereas ligand-induced EGFR signaling blocks it. Constitutive EGFR signaling leads to activation of Met leading to increased invasiveness. We also identify a TAB1-TAK1-NF- B pathway that drives GBM invasion. Ligand-activated EGFR signaling leads to Axl activation and proliferation and decreased GBM invasiveness. In Specific Aim 2: we uncover mechanisms used by EGFR to suppress invasiveness of GBM cells. We test the hypothesis that BIN3 is a major negative regulator of invasion. Ligand-induced EGFR activity upregulates BIN3 and suppresses invasion. We examine the expression patterns of BIN3, BIN3 partners, EGFR and other RTKs networks in GBM. In Specific Aim 3 we examine the biological effects of constitutive vs. ligand induced EGFR–RTK-BIN3 signaling on GBM invasion in an orthotopic mouse model and examine tofacitinib as a treatment that specifically inhibits GBM invasion in ligand-poor GBMs. .