PO.IM02.06 · 免疫学
动态转录重塑和功能适应驱动淋巴瘤的恶性进展
Dynamic transcriptional remodeling and functional adaptation drive malignant progression in lymphoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：淋巴瘤进展由恶性 B 细胞与肿瘤微环境之间的动态相互作用所塑造，产生显著的转录和功能异质性。为定义驱动这一适应性演化的机制，我们建立了一种可移植的癌基因驱动淋巴瘤模型，能够在连续肿瘤传代过程中受控地追踪克隆演化、转录重塑和功能适应。
方法：将来自转基因荷淋巴瘤小鼠的原发肿瘤连续移植入同基因宿主，产生早期（P0）、中期（P2）和晚期（P4）阶段。使用单细胞转录组学、CNV 推断（inferCNV）以及通路水平建模（Seurat/Scanpy、GSVA、Enrichr、基于 DrugBank 的预测）来定义恶性细胞和微环境的演化以及新出现的易感性。
结果：连续传代产生了与恶性演化一致的渐进性转录多样化。P0 肿瘤表现出增殖激活和代谢预激，而 P4 肿瘤则发展出免疫抑制、血管生成和应激适应程序，与晚期人类 B 细胞淋巴瘤的特征相吻合。一个关键发现是 P4 中一个统一的应激-存活模块，以缺氧响应、UPR 相关和代谢重编程通路为特征，同时增殖依赖性降低。此外还出现了性别特异性通路偏倚，包括细胞因子/趋化因子信号和代谢检查点利用。药物反应推断鉴定出传代特异性易感性，其中 P4 对氧化应激缓冲、脂质代谢和 UPR 节点的抑制剂表现出更高敏感性。
未来方向：多参数流式细胞术、免疫组织化学和空间分析正在进行中，以验证谱系重编程、基于 CNV 的恶性分类以及通路激活状态。
结论：在该模型中，恶性进展由迭代性转录重编程和受微环境选择塑造的功能适应所驱动。P4 最准确地重现了晚期疾病的转录组和功能特征，使其成为研究治疗耐药性和鉴定侵袭性 B 细胞淋巴瘤中新出现易感性的理想临床前平台。
查看英文原文 English abstract
Background: Lymphoma progression is shaped by dynamic interactions between malignant B cells and the tumor microenvironment, generating marked transcriptional and functional heterogeneity. To define mechanisms driving this adaptive evolution, we developed a transplantable oncogene-driven lymphoma model enabling controlled tracking of clonal evolution, transcriptional remodeling, and functional adaptation across serial tumor passages.
Methods: Primary tumors from transgenic lymphoma-bearing mice were serially propagated into syngeneic hosts, generating early (P0), intermediate (P2), and advanced (P4) stages. Single-cell transcriptomics, CNV-inference (inferCNV), and pathway-level modeling (Seurat/Scanpy, GSVA, Enrichr, DrugBank-based prediction) were used to define malignant and microenvironmental evolution and emerging vulnerabilities.
Results: Serial propagation produced progressive transcriptional diversification consistent with malignant evolution. P0 tumors exhibited proliferative activation and metabolic priming, whereas P4 tumors developed immunosuppressive, angiogenic, and stress-adaptive programs mirroring hallmarks of advanced human B-cell lymphoma. A key finding was a unified stress-survival module in P4, marked by hypoxia-responsive, UPR-related, and metabolically rewired pathways, alongside reduced proliferative dependence. Sex-specific pathway biases including cytokine/chemokine signaling and metabolic checkpoint usage also emerged. Drug-response inference identified passage-specific vulnerabilities, with P4 showing heightened sensitivity to inhibitors of oxidative-stress buffering, lipid metabolism, and UPR nodes.
Future Directions: Multiparametric flow cytometry, immunohistochemistry, and spatial profiling are underway to validate lineage reprogramming, CNV-based malignant classifications, and pathway activation states.
Conclusions: Malignant progression in this model is driven by iterative transcriptional reprogramming and functional adaptation shaped by microenvironmental selection. P4 most accurately recapitulates transcriptomic and functional features of advanced disease, making it an optimal preclinical platform for studying therapeutic resistance and identifying emergent vulnerabilities in aggressive B-cell lymphoma.
利益披露 Disclosure
B. Kapadia, None..
A. Roychodhury, None.