UBE2C promotes leptomeningeal dissemination and is a therapeutic target in brain metastatic disease

Abstract

Background Despite current improvements in systemic cancer treatment, brain metastases (BM) remain incurable, and there is an unmet clinical need for effective targeted therapies. Methods Here, we sought common molecular events in brain metastatic disease. RNA sequencing of thirty human BM identified the upregulation of UBE2C, a gene that ensures the correct transition from metaphase to anaphase, across different primary tumor origins. Results Tissue microarray analysis of an independent BM patient cohort revealed that high expression of UBE2C was associated with decreased survival. UBE2C-driven orthotopic mouse models developed extensive leptomeningeal dissemination, likely due to increased migration and invasion. Early cancer treatment with dactolisib (dual PI3K/mTOR inhibitor) prevented the development of UBE2C-induced leptomeningeal metastases. Conclusions Our findings reveal UBE2C as a key player in the development of metastatic brain disease and highlight PI3K/mTOR inhibition as a promising anticancer therapy to prevent late-stage metastatic brain cancer.

Role of UBE2C in Brain Cancer Invasion and Dissemination

“…These studies were chosen based on information on chemotherapeutic resistance, signaling pathways, and mechanisms that shed light onto possible therapeutic strategies. [ [75][76][77][78] Abbreviations. UBE2C: ubiquitin-conjugating enzyme, HER2: human epidermal growth factor receptor 2, p53: tumor suppressor p53, Ki67: marker of proliferation Ki-67, PI3K: phosphoinositide 3-kinase, EGFR: epidermal growth factor receptor, HIF-1α: hypoxia-inducible factor 1-alpha, NSCLC: non-small cell lung carcinomas, TNM: TNM Classification of Malignant Tumors, AKT: AKT serine/threonine kinase, CTLA4: cytotoxic T-lymphocyteassociated protein 4, EMT: epithelial-mesenchymal transition, TFH: T follicular helper cells, FoxM1: Forkhead box M1, AURKB: aurora kinase B, mTOR: mammalian target of rapamycin.…”

“…Recently, Paisana et al reported the association of UBE2C and BM [78]. The authors have demonstrated that UBE2C is highly expressed in human BM from different primary tumors in comparison to normal tissues.…”

“…UBE2C overexpression increases migration and invasion of breast and lung cancer cells. In addition, mice orthotopically injected with UBE2C-overexpressing cancer cells develop increased leptomeningeal dissemination, an aggressive phenotype of brain metastatic disease [78]. Another recent study using singlecell RNA sequencing in human BM from diverse cancer types identified UBE2C as a signature gene in the proliferative molecular subgroup [112].…”

“…Recently, it has been shown that dactolisib (PI3K/mTOR inhibitor) effectively treats UBE2C-driven orthotopic mouse xenografts of breast and lung cancer BM. Interestingly, early treatment with oral dactolisib prevents leptomeningeal dissemination in vivo [78].…”