Loss of MNRR1 inhibits spheroid formation and improves survival in an ovarian cancer mouse syngeneic model

Background: Cancer progression requires mechanisms that support proliferation and metastatic capacity. Detached cells must resist anoikis concurrently acquire metabolic flexibility to survive the limiting oxygen nutrients during transit secondary sites. MNRR1 (CHCHD2) is a biorganellar protein, which in mitochondria can bind Bcl-xL enhance its pro-apoptotic function, or respiratory chain complex IV (COXIV) improve mitochondrial respiration. In nucleus, it promotes expression of genes involved biogenesis stress responses. Given these, we hypothesize may be relevant targetable driver curtail spread ovarian cancer. Methods: was knocked-out (KO) mCherry-expressing TKO mouse cancer using CRISPR-Cas9 (TKO R1 KO). Effect on transcriptome determined by RNA sequencing, Gene Ontology enrichment analysis, qPCR. Proteins were quantified western blot. Cells injected intra-peritoneally (i.p.) C57BL/6 mice (n = 8) tumor growth mCherry fluorescence as measure for burden. Results: KO cell line resulted differential 3,691 genes. Eleven out top 25 differentially regulated Biological Processes are associated with cellular locomotion. Network analysis showed 11 genes, focal adhesion extra-cellular matrix (ECM). Thbs4 most expressed (p 1×10−6; FC −8.97) followed Col1a1 =1×10−6; FC= −3.7). qPCR validated sequencing data indeed significantly down-regulated compared parental < 0.0001 p 0.024, respectively) rescued upon re-expression wild-type MNRR1. When cultured ultra-low attachment (ULA) conditions, did not observe significant difference viability but instead observed morphology. Whereas formed densely packed spheroids, cultures ULA grew single non-aggregated cells. I.p. injection delay 0.0125), development ascites 0.04), and, more importantly, improved survival 0.0385) Conclusion: We demonstrate that, addition anti-apoptotic required ECM repertoire spheroid formation. The loss this function sufficient kinetics, carcinomatosis, syngeneic model. These results value targeting patients. No conflict interest.