Harnessing TNF-mediated cell death in cancer

炎症和细胞死亡是具有基本生物学重要性的古老过程，使感染和损伤期间的生存和适应成为可能。肿瘤坏死因子（TNF）是典型的促炎细胞因子，通过其1型受体（TNF- r1）发出细胞存活、细胞增殖或细胞死亡的信号。TNF刺激炎症反应，其“目的”是消除干扰的来源，使宿主适应异常情况，并最终恢复组织的功能和稳态。然而，当不受控制时，炎症可以驱动慢性重塑和组织修复，从而导致慢性炎症性疾病、癌症和治疗失败。该应用程序的主要思想是，肿瘤的细胞存活和适应机制至少在一定程度上是由癌症相关炎症支持的，并且可以通过将TNF反应从促炎症转变为细胞死亡来成功靶向。尽管有明确的证据表明TNF可以发出细胞存活和死亡的信号，但在不同生物学结果之间转换的机制仍然难以捉摸。这是很重要的，因为它的解决和假定的治疗干预，将允许癌症相关炎症转移到细胞死亡的激活。我们提出这一建议的出发点是关于tnf信号传导和细胞死亡调控的大量新数据。我们发现cIAP1的ub受体功能严格控制TNF信号传导，选择性地调节TNF的促死亡作用，而不抑制NFkB途径。我们的初步数据表明，cIAP1的ub结合域的点突变可改变TNF对细胞死亡的反应，并完全阻止肿瘤发生。在这里，我们建议使用小鼠模型、成像和生化方法来解读cIAP1的ub受体功能如何调节TNF诱导的细胞死亡，以及TNF反应从促炎症转变为细胞死亡是否会导致肿瘤永久消退。tnf超家族细胞因子是程序性坏死（坏死性下垂）的典型诱导剂。尽管触发肿瘤细胞坏死的抗癌疗法可能对克服细胞凋亡抵抗特别有吸引力，因为tnf诱导的坏死下垂也促进炎症，而不受调节的炎症也可以支持肿瘤发生，但仔细检查刺激tnf诱导的坏死的生理和病理后果将是重要的。目前，还没有明确的证据表明坏死对癌症是有益还是有害。在这里，我们将确定在癌症中操纵TNF信号的治疗机会和病理后果。鉴于TNF在人类疾病核心的多种病理过程中发挥着重要作用，我们的研究结果将为治疗干预策略提供新的途径。

Inflammation and cell death are ancient processes of fundamental biological importance that enable survival and adaptation during infection and injury. Tumour necrosis factor (TNF) is the prototypical proinflammatory cytokine that signals, through its type 1 receptor (TNF-R1), either cell survival, cell proliferation or cell death1. TNF stimulates an inflammatory response whose 'purpose' is to remove the source of the disturbance, allowing the host to adapt to an abnormal condition, and, ultimately, to restore functionality and homeostasis to the tissue. However, when deregulated, inflammation can drive chronic remodelling and tissue repair, which contributes to chronic inflammatory diseases, cancer and treatment failure. The principle idea addressed by this application is that cell survival and adaptation mechanisms of tumours are supported, at least in part, by cancer-related inflammation, and that this can be successfully targeted by switching the TNF response from pro-inflammation to cell death. Despite clear evidence that TNF can signal cell survival and death, the mechanisms that can switch between the distinct biological outcomes remain elusive. This is important as its resolution, and putative therapeutic intervention, would allow the diversion of cancer-related inflammation into activation of cell death. Our starting point for this proposal is substantial new data on the regulation of TNF-signalling and cell death. We identified that the Ub-receptor function of cIAP1 critically controls TNF signalling, selectively regulating the pro-death effects of TNF, without inhibiting the NFkB pathway. Our preliminary data indicate that a point mutation in the Ub-binding domain of cIAP1 switches the TNF response to cell death, and completely blocks tumorigenesis. Here, we propose to use mouse models, imaging, and biochemical approaches to decipher how the Ub-receptor function of cIAP1 regulates TNF-induced cell death, and whether switching the TNF response from pro-inflammation to cell death causes tumours to permanently regress. Cytokines of the TNF-superfamily are classic inducers of programmed necrosis (necroptosis). Although anticancer therapies that trigger the necrotic death of tumour cells may be particularly attractive to overcome apoptosis resistance, because TNF-induced necroptosis also facilitates inflammation, and deregulated inflammation can also support tumorigenesis, it will be important to carefully examine the physiological and pathological consequence of stimulating TNF-induced necrosis. At present, there is no clear evidence to indicate whether necrosis is beneficial or harmful in cancers. Here we will determine the therapeutic opportunities and pathological consequences of manipulating TNF signalling in cancer.Given that TNF plays an eminent role in diverse pathological processes at the core of human diseases, our findings will provide new avenues for therapeutic intervention strategies.