PO.TB07.01 · 肿瘤生物学
组织转谷氨酰胺酶（TG2）与CD24之间的功能性串扰增强高级别浆液性卵巢癌的癌症干细胞特征和治疗耐药性
The functional crosstalk between tissue transglutaminase (TG2) and CD24 enhances cancer stem cell traits and therapy resistance in high grade serous ovarian cancer
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摘要 Abstract
中文摘要
高级别浆液性卵巢癌（HGSOC）仍是最致命的妇科恶性肿瘤之一，这在很大程度上归因于驱动疾病进展的持续存在的癌症干细胞（CSC）。我们的数据揭示，组织转谷氨酰胺酶2（TG2）通过其与纤连蛋白（FN）和整合素的相互作用，激活包括Wnt信号在内的致癌通路，从而促进干性和铂类耐药，是卵巢癌干细胞（OCSC）生物学的核心介导因子。我们进一步发现，TG2与免疫调节受体CD24协作，将OCSC锚定于腹膜器官，促进早期转移性植入和腹水形成。为在治疗上破坏这一轴，我们合成了一种选择性肽抑制剂（BP），可阻断TG2-FN相互作用，并开发了一种CD24中和抗体（CD24-Ab），两者均可在临床前模型中抑制CSC功能。随后，我们将这两种手段结合成单一的首创同类抗体-肽偶联物APC（CD24-Ab-TG2-BP），旨在同时破坏CD24信号和TG2介导的CSC-肿瘤微环境（TME）相互作用。HGSOC的TCGA分析显示，TG2和CD24 mRNA分别在3%和2%的病例中扩增。流式细胞术分别在OVCAR4和OVCAR5细胞中证实了强健的TG2（58%、51%）和CD24（98%、100%）表达，并有大量共表达（55%、45%）。APC处理显著下调CSC相关标志物（NANOG、OCT4、SOX2、ALDH1A1）并破坏球体结构。共免疫沉淀在SKOV3和OVCAR4细胞中证明了特异性的TG2-CD24相互作用，而生化分级分离将该复合物定位于脂筏微结构域——整合受体和下游致癌效应因子的信号平台。在卵巢癌异种移植模型中，与IgG对照相比，APC处理显著降低了肿瘤体积（0.22 ± 0.11 mm³ vs. 1.7 ± 1.1 mm³；N=5，P<0.001）、肿瘤重量（0.64 ± 0.21 gm vs. 1.53 ± 0.46 gm；N=5，P<0.01）和转移（5.3 + 3.6 vs. 10 + 3.6；N=5，P<0.001），从而证明了强效的抗肿瘤疗效。总之，这些发现将一个脂筏限定的TG2-CD24复合物鉴定为HGSOC中OCSC维持和化疗耐药的新型驱动因子。用APC靶向这一相互作用可有效破坏CSC-TME串扰并抑制肿瘤进展，确立TG2/CD24轴为克服HGSOC耐药和复发的新型治疗脆弱点。
查看英文原文 English abstract
High-grade serous ovarian cancer (HGSOC) remains one of the most lethal gynecologic malignancies, largely due to persistent cancer stem cells (CSCs) that drive disease progression. Our data revealed that tissue transglutaminase 2 (TG2) is a central mediator of OCSC biology through its interaction with fibronectin (FN) and integrins, activating oncogenic pathways, including Wnt signaling, that promote stemness and platinum resistance. We further identified that TG2 cooperates with the immune-regulatory receptor CD24 to anchor OCSCs to peritoneal organs, facilitating early metastatic implantation and ascites formation. To therapeutically disrupt this axis, we synthesized a selective peptide inhibitor (BP) that blocks the TG2-FN interaction and developed a CD24-neutralizing antibody (CD24-Ab), each of which suppresses CSC function in preclinical models. We then combined these modalities into a single first-in-class antibody-peptide conjugate, APC (CD24-Ab-TG2-BP), designed to simultaneously disrupt CD24 signaling and TG2-mediated CSC-tumor microenvironment (TME) interactions. TCGA analysis of HGSOC revealed TG2 and CD24 m RNA amplification in 3% and 2% of cases, respectively. Flow cytometry confirmed robust TG2 (58%, 51%) and CD24 (98%, 100%) expression, with substantial co-expression (55%, 45%) in OVCAR4 and OVCAR5 cells, respectively. APC treatment significantly downregulated CSC-associated markers (NANOG, OCT4, SOX2, ALDH1A1) and disrupted spheroid architecture. Co-immunoprecipitation demonstrated a specific TG2-CD24 interaction in SKOV3 and OVCAR4 cells, while biochemical fractionation localized the complex to lipid raft microdomains, signaling platforms that integrate receptors and downstream oncogenic effectors. In OC xenograft models, treatment with APC significantly reduced tumor volume (0.22 ± 0.11 mm³ vs. 1.7 ± 1.1 mm³; N =5, P < 0.001), tumor weight (0.64 ± 0.21 gm vs. 1.53 ± 0.46 gm; N =5, P < 0.01), and metastasis (5.3 + 3.6 vs. 10 + 3.6; N =5, P < 0.001) when compared with IgG controls, thus demonstrating potent anti-tumor efficacy. Collectively, these findings identify a lipid raft-restricted TG2-CD24 complex as a novel driver of OCSC maintenance and chemoresistance in HGSOC. Targeting this interaction with APC effectively disrupts CSC-TME crosstalk and suppresses tumor progression, establishing TG2/CD24 axis as a novel therapeutic vulnerability for overcoming resistance and recurrence in HGSOC.
利益披露 Disclosure
R. Nagare, None..
H. Begum, None..
B. Wamba, None..
J. Tushir-Singh, None..
F. Pin, None.