IRAK2 depletion renders breast cancer stem cells non-tumorigenic via differentiation

IRAK2 缺失使乳腺癌干细胞通过分化变得非致瘤性

• 批准号: 407869199
• 负责人: Privatdozent Dr. Jochen Maurer
• 金额: --
• 依托单位: Klinik für Gynäkologie und Geburtsmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/407869199?language=en
• 关键词: IRAK2; depletion; renders; breast; cancer

In recent years, developmental pathways and traits have gained interest in the search of novel agents for cancer therapy. In addition, our established models for investigative/experimental designs are based on developmental concepts. In particular, cancer cells with the characteristics of stem cells have been of interest in hematopoietic malignancies as well as solid tumors, influencing the way we define tumorigenesis.These so called cancer stem cells (CSCs) are thought to be the motor of tumor growth and expansion. They are chemoresistant, sometimes quiescent and the origin of metastasis. Several surface markers are discussed as specific for a given cancer tissue type and screening efforts are underway to target these cells in particular. Nevertheless most efforts lack a clear foundation, because CSCs are hard to isolate, propagate or purify. Additionally, classical targeting strategies aim to kill these cells with the known side effects of current medical therapies.We identified a novel method to isolate and cultivate CSCs from human patient tumors of triple negative breast cancer (TNBC). The CSCs can be expanded for analytical purpose and to identify modes of action of target genes and novel therapies. The cells are highly tumorigenic with as few as 1000 cells recapitulating the patient’s tumor of origin in immunocompromised animals to a likeness making it hard for a pathologist to tell patient and xenograft apart. In parallel, we identified kinases responsible for cancer stem cell maintenance in triple negative breast cancer. Among others, we identified kinases ALPK1 and ERN1 as gatekeepers for cancer stem cell self-renewal and differentiation, showing for the first time that knockdown of these kinases elicits a differentiation response in bipotent tumor initiating cells of TNBC. This luminal-like differentiation rendered the cells incapable of tumor formation. One additional kinase identified in said screen was Interleukin-1 receptor-associated kinase-like 2 (IRAK2). Like ERN1 and ALPK1, IRAK2 was capable of driving cells towards a luminal fate. Interestingly, IRAK2 is also one of the most highly enriched genes in CSC cultures from primary TNBC patients varying in intensity from patient to patient. In this proposal we want to investigate the role of IRAK2 in maintenance of CSCs from TNBC, elucidate its mode of action and its clinical significance and finally identify novel therapeutics targeting IRAK2. Using our unique human CSC cultures from TNBC patients, we will generate direct applicability to the clinic and fulfill the medical need. The idea to manipulate stemness features of a given cancer rather than aiming for selective cell death opens up alternative treatment possibilities which might benefit the patient in the years to come.

近年来，发展途径和特征引起了人们对寻找癌症治疗新药的兴趣。此外，我们建立的研究/实验设计模型是基于发展概念的。特别是，具有干细胞特征的癌细胞在造血系统恶性肿瘤和实体瘤中引起了人们的兴趣，影响了我们定义肿瘤发生的方式。这些所谓的癌症干细胞（CSC）被认为是肿瘤生长和扩张的动力。它们具有化学抗性，有时处于静止状态，是转移的起源。讨论了几种针对特定癌症组织类型的表面标志物，并且正在进行针对这些细胞的筛选工作。然而，大多数努力缺乏明确的基础，因为 CSC 很难分离、传播或纯化。此外，经典的靶向策略旨在通过当前医学疗法已知的副作用来杀死这些细胞。我们确定了一种从三阴性乳腺癌 (TNBC) 人类患者肿瘤中分离和培养 CSC 的新方法。 CSC 可以扩展用于分析目的并确定靶基因的作用模式和新疗法。这些细胞具有高度致瘤性，只有 1000 个细胞在免疫功能低下的动物中再现了患者的肿瘤起源，这使得病理学家很难区分患者和异种移植物。与此同时，我们鉴定了负责三阴性乳腺癌中癌症干细胞维持的激酶。其中，我们确定激酶 ALPK1 和 ERN1 是癌症干细胞自我更新和分化的看门人，首次表明这些激酶的敲低可引发 TNBC 双能肿瘤起始细胞的分化反应。这种管腔样分化使细胞无法形成肿瘤。在所述筛选中鉴定出的另一种激酶是白细胞介素-1受体相关激酶样2 (IRAK2)。与 ERN1 和 ALPK1 一样，IRAK2 能够驱动细胞走向管腔命运。有趣的是，IRAK2 也是原发性 TNBC 患者 CSC 培养物中富集程度最高的基因之一，其强度因患者而异。在本提案中，我们希望研究 IRAK2 在维持 TNBC 的 CSC 中的作用，阐明其作用模式及其临床意义，并最终确定针对 IRAK2 的新疗法。利用来自 TNBC 患者的独特人类 CSC 培养物，我们将直接应用于临床并满足医疗需求。操纵特定癌症的干性特征而不是选择性细胞死亡的想法开辟了替代治疗的可能性，这可能在未来几年使患者受益。