Study reveals a new oncogenic role of NBL1 in ovarian cancer metastasis

Ovarian cancer (OC), one of the three most common gynecological malignancies, is characterized by low early detection rates and poor prognosis. Patients with OC face a high risk of developing transcoelomic metastasis—the spread of cancer cells within the abdominal cavity—during the early stages of the disease, a process strongly linked to poor survival outcomes. However, the underlying mechanisms of how OC cells spread from the primary tumor to distant sites have remained elusive.

In a recent study published in Genes & Diseases, researchers from Tianjin Medical University, Tianjin Central Hospital of Gynecology Obstetrics, and Nankai University, employed CRISPR-based large-scale genetic screening alongside an orthotopic ovarian cancer mouse model with gene knockout cells to unravel the molecular mechanisms underlying OC.

Using a genome-wide in vivo CRISPR/Cas9 screening approach combined with patient-derived transcriptomic datasets, researchers identified neuroblastoma suppressor of tumorigenicity 1 (NBL1) as one of the most critical genes promoting transcoelomic metastasis. NBL1 was found to be significantly overexpressed in metastatic ovarian tumors, with expression levels strongly correlating with advanced clinical stage and poor survival outcomes.

Further experiments by the team revealed that NBL1 promotes OC cell proliferation, migration, invasion, and resistance to apoptosis through dual mechanisms: i) direct activation of Jak/Stat3 signaling via physical interaction and ii) suppression of anti-tumor immunity by limiting T cell infiltration. Notably, the Stat3 inhibitor Wp1066 was shown to block NBL1-driven metastasis, reversing its effects on cell proliferation, migration, and epithelial-mesenchymal transition (EMT), both in in vitro and in vivo models.

In conclusion, this study reveals a previously unrecognized oncogenic role of NBL1 in OC metastasis through Jak/Stat3 pathway activation. Its strong association with poor prognosis, combined with reversibility by Stat3 inhibitors, positions NBL1 as both a prognostic biomarker and a promising therapeutic target.