PO.PR02.03 · 预防研究
STAT3信号的时间依赖性决定代谢功能障碍相关脂肪性肝炎中的肝癌发生
Temporal dependency of STAT3 signaling dictates hepatocarcinogenesis in metabolic dysfunction-associated steatohepatitis
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
背景：代谢功能障碍相关脂肪性肝炎（MASH）正迅速超越病毒性和酒精性病因，成为肝细胞癌（HCC）的主要病因。尽管如此，支配从代谢损伤向恶性转化的分子检查点仍知之甚少。过度激活的STAT3已被认为与脂质失调、炎症、纤维化及致癌信号有关。然而，其在MASH向HCC进展过程中的动态调控仍不明确。
方法：我们对患病的小鼠和人肝组织进行了纵向分析，以绘制STAT3信号在各疾病阶段的动态变化。利用STAM模型，我们施用了一种靶向肝细胞、GalNAc偶联的Dicer底物siRNA（GalNAc-STAT3），以在不同疾病阶段选择性沉默STAT3：（i）早期MASH和（ii）肿瘤起始后。通过组织病理学和血清蛋白质组学评估疾病结局。采用空间转录组学和免疫表型分析来解析微环境特异性和亚型特异性反应。
结果：STAT3抑制表现出显著的阶段特异性效应。在恶性转化之前的早期干预，尽管脂肪变性持续存在，仍显著降低了HCC的起始和肿瘤负荷，表明单纯的脂质蓄积不足以驱动癌变。多组学分析在瘤周区域识别出一种STAT3依赖性、TGF-beta1相关的纤维化和炎症程序，其作为恶性进展的关键分子驱动因素。相比之下，尽管有效抑制了STAT3，晚期干预未能减少肿瘤结节的形成，表明恶性转化后STAT3依赖性的丧失。空间探查进一步揭示了亚型特异性适应性重塑：在谷氨酰胺合成酶（GS）阳性结节中通过代谢再分化实现，而在GS阴性肿瘤中则激活了应激耐受转录程序。
结论：这项工作揭示了STAT3在MASH相关肝癌发生过程中此前未被认识的时间依赖性。STAT3作为早期驱动因素对建立促肿瘤生态位至关重要，但一旦恶性细胞状态出现则可被摒弃。这些发现重新界定了STAT3抑制的治疗窗口，将其定位为早期阶段的拦截策略，而非晚期肿瘤的治疗手段。
查看英文原文 English abstract
Background: Metabolic dysfunction-associated steatohepatitis (MASH) is rapidly surpassing viral and alcoholic etiologies as the leading cause of hepatocellular carcinoma (HCC). Despite so, the molecular checkpoints governing the transition from metabolic injury to malignancy remain poorly understood. Hyperactivated STAT3 has been implicated in lipid dysregulation, inflammation, fibrosis, and oncogenic signaling. However, its dynamic regulation during MASH-to-HCC progression remains undefined.
Methods: We performed longitudinal profiling of diseased mouse and human liver tissues to map STAT3 signaling dynamics across disease stages. Using the STAM model, we administered a hepatocyte-targeting, GalNAc-conjugated Dicer-substrate siRNA (GalNAc-STAT3) to selectively silence STAT3 at distinct disease phases: (i) early MASH and (ii) post-tumor initiation. Disease outcomes were evaluated using histopathology and serum proteomics. Spatial transcriptomics and immune phenotyping were used to resolve microenvironment- and subtype-specific responses.
Results: STAT3 suppression exhibited striking stage-specific effects. Early intervention prior to malignant transformation substantially reduced HCC initiation and tumor burden despite persistent steatosis, demonstrating that lipid accumulation alone is insufficient to drive carcinogenesis. Multi-omics analyses identified a STAT3-dependent, TGF-beta1-associated fibrogenic and inflammatory program in peritumoral regions that acted as a key molecular driver for malignant progression. In contrast, late intervention failed to reduce tumor nodule formation despite effect STAT3 inhibition, indicating loss of STAT3 dependency following malignant transformation. Spatial interrogation further revealed subtype-specific adaptive remodeling through metabolic re-differentiation in glutamine synthetase (GS)-positive nodule, and activated stress tolerance transcriptional programs in GS-negative tumors.
Conclusions: This work uncovers a previously unrecognized temporal dependency of STAT3 during MASH-associated hepatocarcinogenesis. STAT3 is essential as an early driver in establishing pro-tumorigenic niche, but is dispensable once malignant cell states emerge. These discoveries redefine the therapeutic window for STAT3 inhibition, positioning it as an early stage interception strategy rather that treatment for advanced tumors.
利益披露 Disclosure
J. Eu, None..
N. B. Mohamed Salleh, None..
M. Sim, None..
Z. Tan, None..
T. Tan, None..
B. Goh, None..
L. Kong, None.