Dissecting the heterogeneity of tumor-initiating cells in hepatobiliary cancers: molecular characterization and targeting of stemness features

剖析肝胆癌肿瘤起始细胞的异质性：干性特征的分子表征和靶向

• 批准号: 216380486
• 负责人: Professor Dr. Jens U. Marquardt
• 金额: --
• 依托单位: Medizinische Klinik I
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/216380486?language=en
• 关键词: Dissecting; heterogeneity; tumor; initiating; cells

Primary liver cancers (PLCs) are among the most rapidly evolving malignant tumors worldwide. An underlying chronic inflammatory liver disease precedes liver cancer development for several decades and creates a pro-oncogenic microenvironment that renders the liver susceptible for malignant transformation. Depending on the primary cellular targets, a diverse range of different morphological and molecular phenotypes is observed in PLCs that frequently impairs therapeutic progress. In this context, the cancer stem cell (CSC) hypothesis provides a plausible explanation for the resulting tumor heterogeneity and implies a rationale for therapeutic strategies beyond the currently used anti-proliferative agents. Thus, eradication of tumors that follow the hierarchic model would require novel therapeutic strategies that specifically target the CSCs. Therefore, a detailed understanding of key molecular features that drive CSC characteristics is imperative to improve the dismal outcome of PLC patients. In the here presented project, we will focus on different key aspects of CSC-biology in PLCs, including intra-tumoral CSC-heterogeneity, prospective isolation of CSCs as well as therapeutic targeting of stemness features. First, we will develop and evaluate a novel robust and reproducible in vitro model of PLC that closely resembles individual phenotypic and molecular characteristics of individual patients. We will then prospectively isolate purified CSCs from human PLCs and apply next-generation whole transcriptome sequencing to define common molecular features and prognostic implications of PLC-CSCs. Subsequently, we will evaluate the therapeutic potential of targeting the identified signaling pathways for CSC-directed therapeutic approaches by using small molecules as well as RNAi. After successful evaluation of the most promising candidates for molecular targeting we will test the applicability of the obtained results for other solid tumors as well as liver metastasis from different primary cancers. Finally, we will directly test the importance of the tumor microenvironment for the heterogeneity of CSCs in PLC by comparing the molecular profiles of CSCs isolated from different intra-tumoral, peri-tumoral and non-tumorous regions. By the end of these investigations we aim at providing a detailed description of the molecular features of PLC-CSCs and delineate the potential of targeting stemness features to complement the existing therapeutic strategies in PLC.

原发性肝癌（PLC）是全球最快发展的恶性肿瘤之一。一种潜在的慢性炎症性肝脏疾病在肝癌的发展前几十年，并创造了亲密的微环境，使肝脏易受恶性转化。根据主要的细胞靶标，在经常会损害治疗进展的PLC中观察到不同的不同形态和分子表型。在这种情况下，癌症干细胞（CSC）假设为由此产生的肿瘤异质性提供了合理的解释，并意味着除了当前使用的抗增殖药物以外的治疗策略的基本原理。因此，根除遵循层次模型的肿瘤将需要专门针对CSC的新型治疗策略。因此，必须对驱动CSC特征的关键分子特征的详细理解对于改善PLC患者的沮丧结果至关重要。在此处介绍的项目中，我们将重点关注PLC中CSC生物学的不同关键方面，包括肿瘤内CSC杂种性，前瞻性隔离CSC以及对茎特征的治疗靶向。首先，我们将开发和评估一种新型的鲁棒和可重现的PLC体外模型，该模型与单个患者的个体表型和分子特征非常相似。然后，我们将前瞻性地将纯化的CSC与人PLC分离，并应用下一代全转录组测序来定义PLC-CSC的常见分子特征和预后意义。随后，我们将通过使用小分子和RNAi来评估针对CSC定向治疗方法的识别信号通路的治疗潜力。在成功评估了分子靶向最有希望的候选者之后，我们将测试来自不同原发性癌症的其他实体瘤以及肝转移的结果。最后，我们将直接测试肿瘤微环境对PLC中CSC的异质性的重要性，通过比较从不同肿瘤内，肿瘤周期和非肿瘤区域中分离出的CSC的分子谱。在这些研究结束时，我们旨在提供对PLC-CSC的分子特征的详细描述，并描述靶向STEMNESS特征以补充PLC中现有的治疗策略的潜力。

项目成果

Cytoplasmic localization of the cell polarity factor scribble supports liver tumor formation and tumor cell invasiveness

• DOI: 10.1002/hep.29669
• 发表时间: 2018-05-01
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Wan, Shan;Meyer, Anne-Sophie;Breuhahn, Kai
• 通讯作者: Breuhahn, Kai

YAP-dependent induction of UHMK1 supports nuclear enrichment of the oncogene MYBL2 and proliferation in liver cancer cells

• DOI: 10.1038/s41388-019-0801-y
• 发表时间: 2019-04
• 期刊: Oncogene
• 影响因子: 8
• 作者: T. Wei;S. Weiler;M. Tóth;C. Sticht;T. Lutz;S. Thomann;C. de la Torre;B. Straub;S. Merker

Curcumin effectively inhibits oncogenic NF-κB signaling and restrains stemness features in liver cancer.

• DOI: 10.1016/j.jhep.2015.04.018
• 发表时间: 2015-09
• 期刊: Journal of hepatology
• 影响因子: 25.7
• 作者: Marquardt JU;Gomez-Quiroz L;Arreguin Camacho LO;Pinna F;Lee YH;Kitade M;Domínguez MP;Castven D;Breuhahn K;Conner EA;Galle PR;Andersen JB;Factor VM;Thorgeirsson SS
• 通讯作者: Thorgeirsson SS

Functional and genetic deconstruction of the cellular origin in liver cancer

• DOI: 10.1038/nrc4017
• 发表时间: 2015-11-01
• 期刊: NATURE REVIEWS CANCER
• 影响因子: 78.5
• 作者: Marquardt, Jens U.;Andersen, Jesper B.;Thorgeirsson, Snorri S.
• 通讯作者: Thorgeirsson, Snorri S.

The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis

• DOI: 10.1038/s41467-018-07922-3
• 发表时间: 2019-01-08
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Baechler, S. A.;Factor, V. M.;Pommier, Y.
• 通讯作者: Pommier, Y.