Microenvironment Interleukin-17 and Colorectal Cancer Treatment Resistance

 描述(申请人提供)：尽管临床上取得了进展，但结直肠癌(CRC)仍然是全世界与癌症相关的死亡的主要原因。由于结直肠癌治愈的最大障碍之一是术后无法对辅助化疗取得持久的反应，因此分析治疗耐药的机制具有及时和临床意义。肿瘤起始细胞(CICs)参与肿瘤血管生成、侵袭/转移和治疗耐药。我们发现了一种新的现象，即化疗激活了癌症相关成纤维细胞(CAF)，释放了外部信号，主要是白介素17A(IL17A)，它通过增加CRC CIC的增殖、迁移、肿瘤生长和化疗耐药来重塑肿瘤微环境。在体外和体内，IL17A的抑制都减轻了这些影响，这表明这是一个潜在的干预靶点。IL-1刺激导致Act1向IL-17R募集，并在结肠上皮细胞中诱导多种增殖和细胞生存途径(包括NF-kB、JNK、p38、ERK)，但IL17A在CICs中的作用尚不清楚。当评估IL17A在人类中的表达时，我们发现结直肠癌患者的表达有所不同，表达增加与更差的预后相关。这些观察表明IL17A影响患者的预后，但这种影响的细节尚不清楚。基于这一背景，我现在将研究一种关键细胞因子(IL17A)在CIC维持和治疗耐药中的作用。我推测，IL17A来源于肿瘤微环境中激活的CAF，它重塑了细胞层次结构，促进了CIC的维持和治疗耐药。在第一个目标中，我将阐明IL17R-Act1轴增强人CIC肿瘤发生和化疗耐药的分子机制。在第二个目标中，我将利用培养的人CICs和体内的小鼠结直肠癌模型，采用包括化疗、IL17抑制和MEK/ERK抑制在内的联合治疗，确定针对IL17A诱导的结直肠癌信号转导的治疗益处。最后，我将探索IL17在体外人类结直肠癌标本中的作用，以及与遗传和临床特征的相关性，以开发生物标记物。这项拟议的工作将深入了解导致结直肠癌治疗耐药性的分子机制，测试新的治疗组合，并确定适合这些治疗的适当患者群体，所有这些都将导致提高结直肠癌患者存活率的长期目标。

 DESCRIPTION (provided by applicant): Despite clinical advances, colorectal cancer (CRC) remains a leading cause of cancer-related death throughout the world. As one of the greatest barriers to CRC cure is the inability to achieve a durable response to adjuvant chemotherapy after surgery, it is both timely and clinically relevant to dissect the mechanisms underlying therapeutic resistance. Cancer initiating cells (CICs) contribute to tumor angiogenesis, invasion/metastasis, and therapeutic resistance. We identified a novel phenomenon that chemotherapy activates cancer associated fibroblasts (CAFs), with release of extrinsic signals, mainly interleukin 17A (IL17A), which remodels the tumor microenvironment by increasing CRC CIC proliferation, migration, tumor growth, and chemoresistance. These effects were mitigated by IL17A inhibition both in vitro and in vivo, suggesting a potential target for intervention. IL-1 stimulation leads to recruitment of Act1 to IL-17R and elicits multiple proliferative and cell survival pathways (including NF-kB, JNK, p38, ERK) in colon epithelial cells, but the role of IL17A in CICs is uncharacterized. When evaluating IL17A in humans, we found expression varies among CRC patients and increased expression is associated with worse outcomes. These observations suggest IL17A influences patient outcome, but details of this effect are not understood. Based on this background, I will now investigate the role of a critical cytokine (IL17A) in CIC maintenance and therapeutic resistance. I hypothesize that IL17A, derived from activated CAFs in the tumor microenvironment, remodels the cellular hierarchy and promotes CIC maintenance and therapy resistance. In the first aim, I will elucidate the molecular mechanism by which the IL17R-Act1 axis enhances human CIC tumorigenesis and chemoresistance. In the second aim, I will determine the therapeutic benefit of targeting IL17A-induced signaling in CRC using human CICs in culture and in vivo mouse CRC models, employing combination therapies including chemotherapy, IL17 inhibition, and MEK/ERK inhibition. Lastly, I will explore the effects of IL17 in ex vivo human CRC specimens with correlation to genetic and clinical characteristics to develop a biomarker profile. The proposed work will provide insight to molecular mechanisms driving CRC treatment resistance, test novel treatment combinations, and identify an appropriate patient population suited for these treatments, all of which will lead toward the long-term goal of improving survival for CRC patients.