PO.MCB07.03 · 分子与细胞生物学
单细胞多组学分析揭示小细胞肺癌的调控机制
Single-cell multi-omics profiling unveils the regulatory mechanisms of small cell lung cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
小细胞肺癌（SCLC）是一种高度侵袭性的肺癌，预后极差。其肿瘤进展的机制及治疗策略仍知之甚少。为应对这一临床挑战，我们利用单细胞ATAC-RNA多组学分析来研究克隆进展及其调控机制。从胸腔积液（n=22）中采集患者来源的细胞（n=73,546），并分为肿瘤、基质、淋巴样和髓样细胞群。肿瘤细胞沿两条克隆轨迹进展，以ASCL1+和NEUROD1+亚型为特征。源自KEAP1突变患者的ASCL1+细胞激活了NRF2-KEAP1通路和铁死亡。值得注意的是，携带KEAP1突变的患者被诊断为大细胞神经内分泌癌和SCLC。相比之下，NEUROD1+细胞的演化与G蛋白信号传导和Rho GTPase通路的上调以及神经元发育相关。在ASCL1+（FOXA1、KLF2、NR2C1、NRF1）和NEUROD1+（PITX1、RORB）亚型中均识别出肿瘤进展调控因子。这些转录因子的机制识别出了靶基因，一致地反映了肿瘤细胞沿不同轨迹的进展。在肿瘤微环境（TME）细胞中，耗竭T细胞和TREM2+巨噬细胞在生存期较长和治疗后患者中更为普遍。细胞周期相关的癌症纤维化在进展期和生存期较短患者中富集。在研究细胞间相互作用时，ASCL1+肿瘤簇主要通过GAS6和SPP1信号网络与髓样和基质细胞相互作用，而NCAM和NEGF通路通过促进神经内分泌肿瘤细胞内的通讯增强了NEUROD1+肿瘤细胞的功能。本研究描绘了SCLC中不同的克隆轨迹，ASCL1+和NEUROD1+亚型通过特定的调控通路驱动肿瘤进展。关键转录因子被识别为肿瘤演化的关键驱动因素。免疫和基质特征提示免疫耗竭和纤维化显著影响患者生存，凸显了治疗策略和治疗后干预的潜在靶点。
查看英文原文 English abstract
Small cell lung cancer (SCLC) is a highly aggressive lung cancer with an extremely poor prognosis. The mechanisms underlying its tumor progression and therapeutic strategies remain poorly understood. To address this clinical challenge, we utilized single-cell ATAC-RNA multiomic profiling to investigate clonal progression and its regulatory mechanisms. Patient-derived cells (n=73,546) were collected from pleural effusions (n=22) and categorized into tumor, stromal, lymphoid, and myeloid populations. Tumor cells exhibited progression along two clonal trajectories, characterized by ASCL1 + and NEUROD1 + subtypes. ASCL1 + cells, derived from KEAP1 -mutated patients, activated the NRF2-KEAP1 pathway and ferroptosis. Notably, patients with KEAP1 mutations were diagnosed with both large-cell neuroendocrine carcinoma and SCLC. In contrast, NEUROD1 + cell evolution was associated with upregulation of G protein signaling and Rho GTPase pathways, along with neuronal development. Tumor progression regulators were identified in both ASCL1 + ( FOXA1 , KLF2 , NR2C1 , NRF1 ) and NEUROD1 + ( PITX1 , RORB ) subtypes. The mechanisms of these transcription factors identified target genes, which consistently reflected tumor cell progression along distinct trajectories. Among TME cells, exhausted T cells and TREM2 + macrophages were more prevalent in longer-survival and post-treatment patients. Cell-cycle-associated cancer fibrosis was abundant in progression and shorter-survival patients. When investigating cell-cell interactions, ASCL1 + tumor clusters predominantly interacted with myeloid and stromal cells through the GAS6 and SPP1 signaling networks, while NCAM and NEGF pathways enhanced the function of NEUROD1 + tumor cells by promoting communication within neuroendocrine tumor cells. This study delineates distinct clonal trajectories in SCLC, with ASCL1 + and NEUROD1 + subtypes driving tumor progression through specific regulatory pathways. Key transcription factors were identified as pivotal drivers of tumor evolution. Immune and stromal profiles suggest that immune exhaustion and fibrosis significantly impact patient survival, underscoring potential targets for therapeutic strategies and post-treatment interventions.
利益披露 Disclosure
C. Park, None.