Anti-COMMD1 monoclonal antibody, clone 4C4

Downregulated in renal cell carcinoma 1 (DRR1) has important roles in tumor cell growth, neuron survival and spine formation, and was recently shown to bind actin. However, the roles of nuclear DRR1 remain largely unexplored. Here, we identified an interaction between filamentous actin (F-actin) and DRR1 in the nucleus, and demonstrated that copper metabolism MURR1 domain-containing 1 (COMMD1) is another binding partner of DRR1. Accordingly, DRR1, F-actin and COMMD1 were shown to form a complex in the nucleus, and the stability of COMMD1 was enhanced in this complex. Increased nuclear COMMD1 in turn promoted the degradation of NF-kappa B. In addition, DRR1 and COMMD1 suppressed the cyclin D1 expression, G1/S transition and cell proliferation of neuroblastoma cells. The binding between DRR1 and F-actin in the nucleus was required for these events. Consistent with these facts, low expressions of DRR1 were associated with tumorigenesis of human neuroblastoma and its mouse model. This study has thus revealed a novel nuclear complex of F-actin, DRR1 and COMMD1 that is involved in NF-kappa B degradation and cell cycle suppression in neuroblastoma cells.

The shortage of liver organ donors is increasing and the need for viable alternatives is urgent. Liver cell (hepatocyte) transplantation may be a less invasive treatment compared with liver transplantation. Unfortunately, hepatocytes cannot be expanded in vitro, and allogenic cell transplantation requires long-term immunosuppression. Organoid-derived adult liver stem cells can be cultured indefinitely to create sufficient cell numbers for transplantation, and they are amenable to gene correction. This study provides preclinical proof of concept of the potential of cell transplantation in a large animal model of inherited copper toxicosis, such as Wilson's disease, a Mendelian disorder that causes toxic copper accumulation in the liver. Hepatic progenitors from five COMMD1-deficient dogs were isolated and cultured using the 3D organoid culture system. After genetic restoration of COMMD1 expression, the organoid-derived hepatocyte-like cells were safely delivered as repeated autologous transplantations via the portal vein. Although engraftment and repopulation percentages were low, the cells survived in the liver for up to two years post-transplantation. The low engraftment was in line with a lack of functional recovery regarding copper excretion. This preclinical study confirms the survival of genetically corrected autologous organoid-derived hepatocyte-like cells in vivo and warrants further optimization of organoid engraftment and functional recovery in a large animal model of human liver disease.