PO.ET09.09 · 实验与分子治疗
TM4SF20作为支架介导DDR1-IRS4信号通路以驱动PDAC转移，并代表一个可成药的治疗靶点
TM4SF20 scaffolds DDR1-IRS4 signaling to drive PDAC metastasis and represents a druggable therapeutic target
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
胰腺导管腺癌（PDAC）表现出极高的肝转移倾向，这在很大程度上导致其临床预后不佳。然而，专门针对转移进展的治疗策略仍然有限。在本研究中，我们探究了驱动PDAC肝转移的分子机制，并探索了能够抑制转移扩散的治疗方法。利用本中心采集的胰腺癌样本的单细胞测序数据，我们将跨膜4 L六家族成员20（TM4SF20）——一种四跨膜蛋白样跨膜蛋白——鉴定为一种此前未被认识的转移进展驱动因子。TM4SF20在PDAC中显著上调，并在肝转移灶中高度富集。通过整合临床病理数据、TM4SF20敲除小鼠模型、类器官系统以及多个实验平台（包括小动物PET-CT、超声成像、免疫沉淀-质谱和体外激酶实验）的综合分析，我们系统性地验证了TM4SF20在促进PDAC肝转移中的功能作用。在机制上，TM4SF20充当膜"桥接分子"：其胞外结构域结合盘状结构域受体1（DDR1），而其胞内结构域与胰岛素受体底物4（IRS4）相互作用。这种支架作用使DDR1依赖性地在T208位点磷酸化IRS4，从而激活AKT信号级联并增强侵袭和转移表型。用单克隆抗体（alphaTM4SF20）对TM4SF20进行治疗性阻断可破坏DDR1-IRS4复合物的形成，抑制下游信号传导，并减弱PDAC细胞的迁移和侵袭。在这一机制洞察的指导下，我们通过将alphaTM4SF20与拓扑异构酶I抑制剂deruxtecan（DXD）偶联，开发了一种靶向TM4SF20的抗体药物偶联物（TM4SF20-ADC）。TM4SF20-ADC保持了高度的靶点特异性，并表现出强效的抗肿瘤活性，可诱导凋亡、清除转移性TM4SF20阳性细胞，并显著抑制肿瘤生长和肝转移。在已建立肝转移的原位PDAC模型中，TM4SF20-ADC同时消除了原发灶和转移灶，显著减轻了肿瘤负荷并延长了生存期，且无可检测的全身毒性。总之，本研究将TM4SF20鉴定为一个关键的转移驱动因子，并确立了TM4SF20靶向ADC疗法作为PDAC肝转移一种有前景的转化策略。
查看英文原文 English abstract
Pancreatic ductal adenocarcinoma (PDAC) exhibits an exceptionally high propensity for liver metastasis, which critically contributes to its poor clinical outcomes. However, therapeutic strategies specifically targeting metastatic progression remain limited. In this study, we investigated the molecular mechanisms driving PDAC liver metastasis and explored therapeutic approaches capable of suppressing metastatic dissemination. Leveraging single-cell sequencing data from pancreatic cancer samples collected at our center, we identified transmembrane 4 L six family member 20 (TM4SF20), a tetraspanin-like transmembrane protein, as a previously unrecognized driver of metastatic progression. TM4SF20 is markedly upregulated in PDAC and highly enriched within liver metastatic lesions. Through integrative analyses combining clinical pathological data, TM4SF20-knockout mouse models, organoid systems, and multiple experimental platforms-including small-animal PET-CT, ultrasonography, immunoprecipitation-mass spectrometry, and in vitro kinase assays-we systematically validated the functional role of TM4SF20 in promoting PDAC liver metastasis. Mechanistically, TM4SF20 acts as a membrane “bridge molecule”: its extracellular domain binds discoidin domain receptor 1 (DDR1), while its intracellular domain interacts with insulin receptor substrate 4 (IRS4). This scaffolding enables DDR1-dependent phosphorylation of IRS4 at T208, thereby activating the AKT signaling cascade and enhancing invasive and metastatic phenotypes. Therapeutic blockade of TM4SF20 with a monoclonal antibody (alphaTM4SF20) disrupted DDR1-IRS4 complex formation, suppressed downstream signaling, and attenuated PDAC cell migration and invasion. Guided by this mechanistic insight, we developed a TM4SF20-directed antibody-drug conjugate (TM4SF20-ADC) by conjugating alphaTM4SF20 with the topoisomerase I inhibitor deruxtecan (DXD). TM4SF20-ADC retained high target specificity and exhibited potent antitumor activity, inducing apoptosis, depleting metastatic TM4SF20-positive cells, and markedly inhibiting tumor growth and liver metastasis. In orthotopic PDAC models with established liver metastases, TM4SF20-ADC simultaneously eliminated primary and metastatic lesions, significantly reducing tumor burden and extending survival without detectable systemic toxicity. Collectively, this study identifies TM4SF20 as a key metastatic driver and establishes TM4SF20-targeted ADC therapy as a promising translational strategy for PDAC liver metastasis.
利益披露 Disclosure
X. Liu, None..
W. Liu, None..
A. Chang, None..
J. Hao, None.