TNF Signaling, Cell Death and Cancer

Division Of Clinical Sciences - Nci

Investigators

Linked publications & trials

Abstract

The research goal of our laboratory is to understand the molecular mechanism of tumor necrosis factor (TNF) signaling and the regulation of cell death and the role of cell death in tumorigenesis. Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays a critical role in diverse cellular events, including cell proliferation, differentiation, and cell death. TNF is also involved in many types of diseases, including cancer. Inappropriate production of TNF plays a critical role in the pathogenesis of both acute and chronic inflammatory diseases such as septic shock, acquired immunodeficiency syndrome (AIDS), and arthritis. The development of anti-TNFalpha therapy is arguably the most significant achievement in the treatment of autoimmune-diseases, such as rheumatoid arthritis and Crohn's disease. Opposing effects of TNF on cancer have been described: a high dose of TNF (acute inflammation) has anti-neoplastic effects, such as direct cytotoxicity on certain types of cancer, while an endogenous low-dose of TNF (chronic inflammation) promotes cancer development. Studies from many laboratories have demonstrated that the diverse TNF-mediated biological responses are achieved through activating multiple signaling pathways (see below). Although much information about TNF signaling has been obtained in recent years, many molecular aspects of TNF signaling and its role in inflammation and cancer development remain unknown. Therefore, uncovering the molecular mechanism of TNF signaling will not only shed new light on the physiological regulation of TNF function but also help to understand its role in inflammation and cancer development. In last year, we have made several significant contributions to the understanding of the molecular mechanism regulating TNF signaling and the regulation of cell death. In the future, we will continue to investigate the regulation of TNF signaling, particularly the molecular mechanisms of TNF-induced cell death, and to explore the role of cell death in tumorigenesis as specified in the following: Studying the regulation of TNF-induced cell death and the involvement of key cell death regulatory proteins in tumorigenesis Aim1: Investigating the regulation of TNF-induced apoptosis by the novel anti-apoptotic protein, ATIA, and its potential role in tumorigenesis. a) Understanding the underlying mechanism of the anti-apoptotic effect of ATIA. b) Demonstrating the importance of ATIA in tumorigenesis. Aim 2: Identifying and studying novel players in tumor necroptosis and exploring the role of necroptosis in tumorigenesis. Understand the regulation of tumor necroptosis. a) Investigate the mechanism of MLKL-mediated necroptosis. b) identifying new components of tumor necroptosis. Study the role of tumor necrosis in tumor development and tumor metastasis. Recently, we have found that necroptosis of tumor cells leads to tumor necrosis and promotes tumor metastasis. we found that tumor necroptosis is induced by glucose deprivation, but not TNF and that ZBP1, not RIPK1, mediated tumor necroptosis during tumor development in breast cancer models. Most recently, we demonstrated that necroptosis-mediated shedding of cell surface proteins promotes tumor metastasis through inhibiting the anti-tumor activities of T cells (Breast Cancer Research). Importantly, we showed that tumor necroptosis leads to the activation of cell surface proteases ADAMs, which mediate the shedding of tumor cell surface proteins including E-Cadherin. Subsequently, the soluble E-Cadherin binds to the immune inhibitory receptor, KLRG1 on CD8+ cells, resulting in the inhibition of the anti-tumor activity of CD8+ T cells and promoting tumor metastasis. Blocking ADAMs activity with their specific inhibitor or neutralizing KLRG1 will dramatically reduce tumor metastasis in mouse breast caner models. Currently, we are translating our findings to cancer treatment by targeting necroptosis, blocking ADMAs activity or neutralizing KLRG1. For instance, to targeting necroptosis, we are generating PROTACs to eliminate ZBP1 or MLKL to block necroptosis. We also explored the role of necroptosis in COVID-19 pathology as necroptosis is involved in viral infection. Our preliminary data indicated that necroptosis plays a key role in "cytokine storm" during viral infection and COVID19 pathology. Therefore, blocking necroptosis is a potential valuable treatment for cancer metastasis and viral infection. Currently, we are developing potential therapeutics, PROTACs, for treating tumor metastasis by targeting key mediators of necroptosis. We are also exploring the role of necroptosis in the inflammatory response, particularly, "cytokine storm", of COVID-19. For the ATIA project, we found that ATIA is a key factor for tumor growth and could serve as a diagnosis marker of multiple types of cancers.