肺腺癌（LUAD）的组织中常常存在沉稳型（鳞层状）和侵袭性型（微乳头状、实体型和差分不良小叶状）的组织亚型，但其亚型之间及其转变的分子特征尚不清楚。本研究结合空间转录组学和多重免疫组化学技术，阐明了LUAD不同组织亚型的分子特征和细胞可塑性。我们揭示了决定亚型进展的转录重编程和动态细胞信号传导，尤其是缺氧诱导的调控网络。不同的组织亚型表现出分化状态的异质性。另外，我们的结果表明，巨噬细胞是LUAD中最常见的细胞类型，并鉴定了与每个组织亚型独特的肿瘤相关巨噬细胞亚群，这可能促进免疫抑制微环境的形成。我们的结果提供了推动LUAD亚型进展的分子特征的系统性综述，并展示了侵袭性肺腺癌的潜在新治疗策略和靶点。© 2023. 中国科学院分子细胞科学卓越中心。

Indolent (lepidic) and aggressive (micropapillary, solid, and poorly differentiated acinar) histologic subtypes often coexist within a tumor tissue of lung adenocarcinoma (LUAD), but the molecular features associated with different subtypes and their transitions remain elusive. Here, we combine spatial transcriptomics and multiplex immunohistochemistry to elucidate molecular characteristics and cellular plasticity of distinct histologic subtypes of LUAD. We delineate transcriptional reprogramming and dynamic cell signaling that determine subtype progression, especially hypoxia-induced regulatory network. Different histologic subtypes exhibit heterogeneity in dedifferentiation states. Additionally, our results show that macrophages are the most abundant cell type in LUAD, and identify different tumor-associated macrophage subpopulations that are unique to each histologic subtype, which might contribute to an immunosuppressive microenvironment. Our results provide a systematic landscape of molecular profiles that drive LUAD subtype progression, and demonstrate potentially novel therapeutic strategies and targets for invasive lung adenocarcinoma.© 2023. Center for Excellence in Molecular Cell Science, CAS.