TNF Signaling, Cell Death and Cancer

Division Of Clinical Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

In last year, we have made several significant contributions to the understanding of the regulation of necroptosis and the role of necroptosis in inflammation and tumorigenesis. For instance, previously, we found that 1) necroptosis of tumor cells leads to tumor necrosis and promotes tumor metastasis, 2) tumor necroptosis is induced by glucose deprivation, but not TNF, 3) ZBP1, not RIPK1, mediated tumor necroptosis during tumor development in breast cancer models and more importantly, 4) necroptosis-mediated shedding of cell surface proteins promotes tumor metastasis through inhibiting anti-tumor activities of T cells. To prove necroptosis is an important therapeutic target for treating tumor metastasis, we developed MLKL PROTAC, a small molecule that leads to MLKL degradation and blockage of necroptosis, and tested its effect on tumor metastasis in two different preclinical breast cancer mouse models. We found that MLKL PROTAC effectively blocked necroptosis in tumor and tumor metastasis to the lung (manuscript in preparation). Also, to better understand the mechanism of tumor necroptosis, we investigated how NOXA, which is critical for tumor necroptosis upsteram of ZBP1, is regulated and found that ATF4 is a key regulator of NOXA (Frontiers in Cell Death, 2025). We also continue to Investigate the role of the anti-apoptotic protein, ATIA/Vasorin in tumorigenesis and found that ATAIA/Vasorin promotes lung cancer development through regulating mitophagy and lysosome function in tumor cells (Autophagy, 2025 and a manuscript under revision). Most recently, during our study on the role of necroptosis in inflammation and tumorigenesis, we identified a novel soluble Tissue Factor (sTF), which is the key mediator of blood clotting, as the consequence of necroptosis in macrophages and tumor cells. Importantly, our data suggests that sTF plays a key role in thrombosis under different pathological conditions including cancer, sepsis and viral infection (manuscript under revision). Our study suggests that sTF is a novel diagnostic marker of thrombosis and a potential therapeutic target for treating the disease. To do so, we have developed a sTF specific humanized monoclonal antibody. This antibody recognizes sTF specifically. Our research will continue along these lines of research directions. Particularly, the translation of our findings by producing MLKL-PROTAC and sTF specific humanized antibody will potentially yield novel therapeutic drugs for treating tumor metastasis and thrombosis.