Luo Ruihan, Liu Jiajia, Wen Jianguo, Zhou Xiaobo
The University of Texas Health Science Center at Houston.
School of Biomedical Informatics, The University of Texas Health Science Center at Houston.
Res Sq. 2024 Apr 5:rs.3.rs-4085185. doi: 10.21203/rs.3.rs-4085185/v1.
Understanding disease progression and sophisticated tumor ecosystems is imperative for investigating tumorigenesis mechanisms and developing novel prevention strategies. Here, we dissected heterogeneous microenvironments during malignant transitions by leveraging data from 1396 samples spanning 13 major tissues. Within transitional stem-like subpopulations highly enriched in precancers and cancers, we identified 30 recurring cellular states strongly linked to malignancy, including hypoxia and epithelial senescence, revealing a high degree of plasticity in epithelial stem cells. By characterizing dynamics in stem-cell crosstalk with the microenvironment along the pseudotime axis, we found differential roles of ANXA1 at different stages of tumor development. In precancerous stages, reduced ANXA1 levels promoted monocyte differentiation toward M1 macrophages and inflammatory responses, whereas during malignant progression, upregulated ANXA1 fostered M2 macrophage polarization and cancer-associated fibroblast transformation by increasing TGF-β production. Our spatiotemporal analysis further provided insights into mechanisms responsible for immunosuppression and a potential target to control evolution of precancer and mitigate the risk for cancer development.
了解疾病进展和复杂的肿瘤生态系统对于研究肿瘤发生机制和制定新的预防策略至关重要。在此，我们利用来自13个主要组织的1396个样本的数据，剖析了恶性转变过程中的异质性微环境。在癌前病变和癌症中高度富集的过渡性干细胞样亚群中，我们确定了30种与恶性肿瘤密切相关的反复出现的细胞状态，包括缺氧和上皮衰老，揭示了上皮干细胞的高度可塑性。通过沿伪时间轴表征干细胞与微环境相互作用的动态变化，我们发现膜联蛋白A1（ANXA1）在肿瘤发展的不同阶段具有不同作用。在癌前阶段，ANXA1水平降低促进单核细胞向M1巨噬细胞分化和炎症反应，而在恶性进展过程中，上调的ANXA1通过增加转化生长因子-β（TGF-β）的产生促进M2巨噬细胞极化和癌症相关成纤维细胞转化。我们的时空分析进一步深入了解了免疫抑制的机制以及控制癌前病变演变和降低癌症发生风险的潜在靶点。
