Harnessing TNF-mediated cell death in cancer

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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.