PO.TB01.01 · 肿瘤生物学
肌成纤维细胞中SMAD2/3对TIMP-1、VEGF-A和缺氧信号的拮抗性调控塑造了肺癌中组织学类型特异性的血管生成
Antagonistic SMAD2/3 control of TIMP-1, VEGF-A, and hypoxia signaling in myofibroblasts shapes histotype-specific angiogenesis in lung cancer
该海报暂无可下载的资料
AACR 官方页面
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
非小细胞肺癌（NSCLC）在其两种主要组织学亚型——肺腺癌（LUAD）和鳞状细胞癌（LUSC）之间对抗血管生成治疗表现出截然不同的反应，提示血管生成存在组织学类型特异性的调控。癌症相关成纤维细胞（CAF）在NSCLC中通常表现出活化/肌成纤维细胞样表型，并正成为肿瘤进展的关键调节者；然而，它们对血管生成调控的贡献仍未明确。在此，我们研究了NSCLC中的血管生成和缺氧特征，并整合了bulk RNA-seq、scRNA-seq、CAF分泌组谱分析、遗传扰动以及功能性的体外和体内实验，以剖析CAF对促血管生成因子的组织学类型依赖性生产。我们在多个患者队列中观察到，与LUSC相比，LUAD具有更强的血管生成和更少的坏死/缺氧。LUAD-CAF分泌组通过SMAD3依赖性地过量生产关键调节因子（最显著的是TIMP-1和VEGF-A）而被引导向血管生成。我们还揭示了TIMP-1在促进内皮过度分支中一个此前未被认识的作用。相反，LUSC-CAF尽管存在强健的HIF-1α上调和缺氧相关转录程序，却因其对SMAD3的表观遗传抑制和SMAD2的代偿性增加而表现出减弱的血管生成活性。总体而言，这些结果揭示了CAF通过SMAD2/3对TIMP-1、VEGF-A和缺氧信号的相反调控，关键性地塑造了LUAD和LUSC各自不同的血管生成图景。这些结果进一步突显了在LUAD中靶向基质SMAD3/TIMP-1或在LUSC中靶向缺氧和酸中毒等微环境应激的治疗潜力。此外，这些发现为理解NSCLC中组织学类型特异性的播散、免疫逃逸和对抗血管生成治疗反应模式提供了一个生物学框架。
查看英文原文 English abstract
Non-small cell lung cancer (NSCLC) exhibits strikingly different responses to antiangiogenic therapies between its two major histologic subtypes, lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), suggesting an histotype-specific regulation of angiogenesis. Cancer-associated fibroblasts (CAFs) commonly exhibit an activated/myofibroblast-like phenotype in NSCLC, and are emerging as key modulators of tumor progression; however, their contribution to angiogenic control remains undefined. Here, we investigated angiogenesis and hypoxia signatures in NSCLC and integrated bulk RNA-seq, scRNA-seq, CAF secretome profiling, genetic perturbations, and functional in vitro and in vivo assays to dissect the histotype-dependent production of pro-angiogenic factors by CAFs. We observed greater angiogenesis and reduced necrosis/hypoxia in LUAD compared to LUSC across multiple patient cohorts. The LUAD-CAF secretome was primed for angiogenesis through SMAD3-dependent overproduction of key regulators, most notably TIMP-1 and VEGF-A. We also uncovered a previously unrecognized role for TIMP-1 in promoting endothelial hyper-branching. In contrast, LUSC-CAFs displayed attenuated angiogenic activity despite robust HIF-1alpha upregulation and an hypoxia-associated transcriptional program, due to their epigenetic repression of SMAD3 and compensatory increase in SMAD2. Collectively, these results reveal that CAFs critically shape the distinct angiogenic landscapes of LUAD and LUSC through opposing SMAD2/3 regulation of TIMP-1, VEGF-A, and hypoxia signaling. These results further highlight the therapeutic potential of targeting stromal SMAD3/TIMP-1 in LUAD or microenvironmental stressors such as hypoxia and acidosis in LUSC. In addition, these findings provide a biological framework for understanding histotype-specific patterns of dissemination, immune evasion, and response to antiangiogenic therapies in NSCLC.
利益披露 Disclosure
J. Alcaraz, None..
D. Park, None.