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

近年来，人们对寻找新的抗癌药物产生了浓厚的兴趣。此外，我们已建立的调查/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血液系统恶性肿瘤和实体瘤中都很受关注，影响了我们定义肿瘤发生的方式。这些所谓的癌症干细胞(CSCs)被认为是肿瘤生长和扩张的马达。它们是化疗耐药的，有时是静止的，是转移的来源。几种表面标志物被认为是特定癌症组织类型的特异性标记，目前正在进行筛查工作，以特别针对这些细胞。然而，大多数努力缺乏明确的基础，因为CSCs很难分离、繁殖或纯化。此外，经典的靶向策略旨在杀死这些具有已知副作用的细胞。我们发现了一种从三阴性乳腺癌(TNBC)患者肿瘤中分离和培养CSCs的新方法。CSCs可以扩展用于分析目的，并识别目标基因的作用模式和新的治疗方法。这些细胞具有很强的致瘤性，只有1000个细胞将患者起源于免疫缺陷动物的肿瘤重现为相似的细胞，这使得病理学家很难区分患者和异种移植。同时，我们确定了在三阴性乳腺癌中负责维持癌症干细胞的激酶。其中，我们发现ALPK1和ERN1是肿瘤干细胞自我更新和分化的守门人，这是我们首次发现敲除这些激酶可以在具有双潜能的TNBC肿瘤起始细胞中引起分化反应。这种管腔样分化使细胞不能形成肿瘤。在该筛查中发现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能够将细胞推向光明期。有趣的是，在原发TNBC患者的CSC培养中，IRAK2也是高度丰富的基因之一，其强度因患者而异。本研究旨在探讨IRAK2在肿瘤干细胞维持中的作用，阐明其作用模式及其临床意义，并最终发现针对IRAK2的新的治疗方法。使用我们独特的来自TNBC患者的人类CSC培养，我们将产生直接适用于临床并满足医疗需求的产品。操纵给定癌症的干细胞特征而不是以选择性细胞死亡为目标的想法开启了替代治疗的可能性，这可能会在未来几年使患者受益。

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.