ASCL1 is a neuroendocrine lineage-specific oncogenic driver of small cell lung cancer (SCLC), highly expressed in a significant fraction of tumors. However, ∼25% of human SCLC are ASCL1-low and associated with low neuroendocrine fate and high MYC expression. Using genetically engineered mouse models (GEMMs), we show that alterations in Rb1/Trp53/Myc in the mouse lung induce an ASCL1⁺ state of SCLC in multiple cells of origin. Genetic depletion of ASCL1 in MYC-driven SCLC dramatically inhibits tumor initiation and progression to the NEUROD1⁺ subtype of SCLC. Surprisingly, ASCL1 loss promotes a SOX9⁺ mesenchymal/neural crest stem-like state and the emergence of osteosarcoma and chondroid tumors, whose propensity is impacted by cell of origin. ASCL1 is critical for expression of key lineage-related transcription factors NKX2-1, FOXA2, and INSM1 and represses genes involved in the Hippo/Wnt/Notch developmental pathways in vivo. Importantly, ASCL1 represses a SOX9/RUNX1/RUNX2 program in vivo and SOX9 expression in human SCLC cells, suggesting a conserved function for ASCL1. Together, in a MYC-driven SCLC model, ASCL1 promotes neuroendocrine fate and represses the emergence of a SOX9⁺ nonendodermal stem-like fate that resembles neural crest.

中文翻译：

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ASCL1 抑制小细胞肺癌中的 SOX9+ 神经嵴干样状态

ASCL1 是小细胞肺癌 (SCLC) 的神经内分泌谱系特异性致癌驱动因素，在大部分肿瘤中高度表达。然而，约 25% 的人类 SCLC 为 ASCL1 低水平，并与低神经内分泌命运和高 MYC 表达相关。使用基因工程小鼠模型 (GEMM)，我们发现小鼠肺中Rb1/Trp53/Myc的改变会在多个起源细胞中诱导 SCLC 的ASCL1 ^+状态。MYC 驱动的 SCLC 中 ASCL1 的基因缺失可显着抑制肿瘤的发生和进展为 NEUROD1 ⁺ SCLC 亚型。令人惊讶的是，ASCL1 缺失促进了 SOX9 ⁺间充质/神经嵴干样状态以及骨肉瘤和软骨样肿瘤的出现，其倾向受到起源细胞的影响。ASCL1 对于关键谱系相关转录因子 NKX2-1、FOXA2 和 INSM1 的表达至关重要，并抑制体内参与 Hippo/Wnt/Notch 发育途径的基因。重要的是，ASCL1 抑制体内 SOX9/RUNX1/RUNX2 程序以及人 SCLC 细胞中 SOX9 的表达，表明 ASCL1 具有保守功能。在 MYC 驱动的 SCLC 模型中，ASCL1 共同促进神经内分泌命运并抑制类似于神经嵴的 SOX9 ^{+非内胚层干样命运的出现。}