A NEURAL TRANSCRIPTION FACTOR IN LUNG CANCER EVOLUTION

这项资助提案的重点是转录因子，人类无毛鳞片同源物-1（hASH 1）在小细胞肺癌（SCLC）演变中的关键作用。 与其他三种主要类型的肺癌不同，SCLC以神经和神经内分泌（NE）特征的表达为特征。 HASH 1是果蝇achaete-scute复合物的人类对应物，该复合物是基本螺旋环螺旋转录因子的保守家族，其对于未分化前体的原始成神经细胞的定型至关重要。 在哺乳动物发育中，ASH 1（啮齿动物中称为MASH 1）对于交感肾上腺、肠、嗅觉、视网膜和脑交感神经元的正常分化至关重要。 我们最近发现，正常胎儿肺中的ASH 1仅限于肺NE细胞。 此外，ASH 1的转基因敲除导致肺NE细胞分化完全失败，并在出生时导致致命的呼吸功能不全。 肺损伤模型的初步研究表明hASH 1在增生性肺NE细胞的募集中起重要作用。 在广泛的肺癌表型中，hASH 1表达与NE表型标记物严格一致。 我们发现，从培养的SCLC细胞的hASH 1蛋白的耗尽导致NE标记物表达的相当的减少，和凋亡分数的增加。 我们研究了一种新的转基因模型，其中hASH 1靶向肺克拉拉细胞，使用细胞特异性CC 10启动子。 这些小鼠发生涉及CC 10反应性细胞的远端气道进行性增生。 值得注意的是，hASH 1与SV 40 T抗原有效合作，促进这些靶细胞中的恶性转化和NE肿瘤。总的来说，这些发现表明，hASH 1可能是关键的小细胞肺癌从肺NE前体细胞的演变。 我们提出的一系列研究现在试图确定：1）hASH 1和相关的原神经转录因子如何在肺癌发生的新模型中发挥作用; 2）hASH 1的转录靶点是什么，与肺癌的演变有关; 3）hASH 1调节如何通过Notch途径在SCLC细胞中改变。 这些研究将提供对hASH 1在SCLC发病机制中作用的更全面的理解，可能导致在新的治疗策略中利用SCLC肿瘤的特定脆弱性。

This grant proposal focuses on the critical role of the transcription factor, human achaete-scute homolog-1 (hASH1) in the evolution of small cell lung cancer (SCLC). Unlike the other three major types of lung cancer, SCLC is distinguished by expression of neural and neuroendocrine (NE) features. HASH1 is a human counterpart to the Drosophila achaete-scute complex, a conserved family of basic helix loop helix transcription factors that are essential for commitment of primitive neuroblasts from undifferentiated precursors. In mammalian development, ASH1 (termed MASH1 in rodents) is essential for normal differentiation of sympathoadrenal, enteric, olfactory, retinal, and brain sympathetic neurons. We have recently shown that ASH1 in the normal fetal lung is restricted to lung NE cells. Furthermore, transgenic knockout of ASH1 results in a complete failure of lung NE cells to differentiate and causes fatal respiratory insufficiency at birth. Preliminary studies from lung injury models suggest an important role for hASH1 in the recruitment of hyperplastic lung NE cells. Across a broad spectrum of lung cancer phenotypes, hASH1 expression is strictly concordant with NE phenotypic markers. We found that depletion of hASH1 protein from cultured SCLC cells resulted in a comparable reduction of NE marker expression, and an increase in apoptotic fraction. We have studied a new transgenic model in which hASH1 is targeted to lung Clara cells, using a cell-specific CC10 promoter. These mice develop progressive hyperplasia of their distal airway involving the CC10-reactive cells. Remarkably, hASH1 cooperates potently with the SV40 T-Antigen to promote malignant transformation and NE tumors in these target cells. Collectively, these findings indicate that hASH1 may be critical in the evolution of SCLC from lung NE precursor cells. Our proposed series of studies now seek to determine: 1) How hASH1 and related proneural transcription factors function in novel models of lung carcinogenesis; 2) What are the transcriptional targets of hASH1, relevant to the evolution of lung cancer, and 3) How hASH1 regulation, via the Notch pathway, may be altered in SCLC cells. These studies will provide a more comprehensive understanding of hASH1 action in SCLC pathogenesis, potentially leading to exploitation of specific vulnerabilities of SCLC tumors in novel treatment strategies.