The role of the EMT-inducer Zeb1 in the invasive tumor stroma during colon cancer progression

EMT诱导剂Zeb1在结肠癌进展过程中侵袭性肿瘤基质中的作用

• 批准号: 428418430
• 负责人: Professor Dr. Thomas Brabletz
• 金额: --
• 依托单位: Georg-Speyer-Haus, Institut für Tumorbiologie und experimentelle Therapie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/428418430?language=en
• 关键词: role; EMT; inducer; Zeb1; invasive

Malignant tumor progression depends on the (transient) acquisition of invasive cellular traits, but we still do not fully understand the underlying regulatory mechanisms. TGFß signaling plays diverse roles during colorectal carcinoma (CRC) progression and may act as an early tumor suppressor or later control invasion and metastasis. In addition, TGFß critically influences the tumor microenvironment, e.g. by recruitment of cancer-associated fibroblasts (CAFs). A high fibroblast content is associated with poor tumor prognosis and CAFs may promote tumor growth directly or indirectly by causing immunosuppression. However, it is currently unknown, which specialized fibroblast populations are involved, and how their formation and plasticity is controlled. Zeb1 has been identified as key downstream factor of TGFβ and master regulator of epithelial-mesenchymal transition (EMT) in tumor cells. In addition, Zeb1 shows prominent expression in a subset of CAFs. Here, we have established tissue-specific knock-out and co-culture/transplantation models to address the role of Zeb1 in CAFs. Our preliminary results show that fibroblast-specific depletion of Zeb1 enhances primary tumor growth by attenuating a tumor-suppressive environment in a colitis-associated cancer model. Co-culture experiments using tumor organoids showed altered niche function and impaired plasticity of Zeb1 deficient fibroblasts. We will characterize the impact of stromal Zeb1 on the tumor microenvironment using invasive mouse models of colon cancer. Fibroblast subtypes and immune cell recruitment will be studied by single cell RNA sequencing. Organoid co-culture and transplantation models will be used for mechanistic dissection of the paracrine cell interactions. Subsequently we will use human CRC samples and clinical data sets to test whether modulation of ZEB1-dependent fibroblast plasticity may offer a therapeutic option.

恶性肿瘤的进展取决于侵袭性细胞特征的（短暂）获得，但我们仍然不完全了解 TGFβ 信号在结直肠癌 (CRC) 进展过程中发挥不同作用，并可能充当早期肿瘤抑制因子或后期控制。此外，TGFβ 通过招募癌症相关成纤维细胞 (CAF) 来严重影响肿瘤微环境。高成纤维细胞含量与肿瘤预后不良相关。 CAF 可能通过引起免疫抑制来直接或间接促进肿瘤生长，但目前尚不清楚哪些特化成纤维细胞群参与其中，以及 Zeb1 的形成和可塑性如何被确定为 TGFβ 的关键下游因子和上皮细胞的主要调节因子。 -肿瘤细胞中的间质转化（EMT）此外，Zeb1 在 CAF 子集中表现出显着的表达，在此，我们建立了组织特异性敲除和共培养/移植模型。我们的初步结果表明，在结肠炎相关癌症模型中，成纤维细胞特异性去除 Zeb1 可通过减弱肿瘤抑制环境来增强原发性肿瘤的生长，而使用肿瘤类器官的共培养实验显示了微生境功能的改变。 Zeb1 缺陷的成纤维细胞的可塑性受损 我们将使用结肠癌的侵袭性小鼠模型来表征基质 Zeb1 对肿瘤微环境的影响。我们将通过单细胞 RNA 测序来研究亚型和免疫细胞招募，并使用类器官共培养模型来对旁分泌细胞相互作用进行机械剖析，随后我们将使用人类 CRC 样本和临床数据集来测试 ZEB1 是否受到调节。依赖的成纤维细胞可塑性可能提供一种治疗选择。