Ovarian cancer represents the most lethal gynecological malignancy, with most patients presenting peritoneal metastasis at diagnosis and demonstrating poor therapeutic response. The five-year survival rate for advanced-stage patients remains below 25%. A recent breakthrough study has identified critical drivers of metastatic progression, offering new therapeutic targets. The research focuses on epithelial-mesenchymal transition (EMT), a fundamental process conferring cellular plasticity and metastatic potential to cancer cells, which leads to accelerated peritoneal dissemination and worsened clinical outcomes. While the pivotal role of EMT in metastasis is well-established, targetable drivers of this process remain elusive. Conventional EMT transcriptional regulators pose challenges for pharmacological intervention due to their functional redundancy and essential roles in tissue homeostasis. Consequently, the identification of novel non-transcriptional regulators has emerged as a crucial strategy to overcome current limitations in EMT-targeted therapy.
Key findings of the study include:

1. Through integrative analysis of data from The Cancer Genome Atlas Program (TCGA) encompassing 20 cancer types and over 8,000 patient samples, combined with robust master regulator (MR) algorithm and Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNE), we identified DNM1 as a novel non-transcriptional regulator. This endocytosis-related gene showed significantly elevated expression in advanced-stage and mesenchymal subtype patients, correlating strongly with shorter progression-free survival and post-relapse survival.
2. Functional validation demonstrated:

In vitro: DNM1 silencing markedly reduced mesenchymal characteristics and migratory capacity in highly metastatic ovarian cancer cells, accompanied by decreased N-cadherin expression. Conversely, DNM1 overexpression in non-metastatic cells induced aggressive phenotypes and upregulated N-cadherin.
In vivo: DNM1 knockdown significantly attenuated peritoneal metastasis in mouse models, confirming its role in metastatic colonization. Mechanistically, DNM1 regulates EMT progression, cell polarity and migration by controlling N-cadherin endocytosis and recycling.

3. Integrated ATAC-seq and RNA-seq analyses revealed that beta-1,3-galactosyltransferase 1(B3GALT1) upregulation in non-metastatic cells may counteract EMT by inhibiting N-cadherin recycling.
4. Metastatic cells exhibited enhanced nanoparticle uptake sensitivity due to DNM1-mediated endocytosis activation, suggesting potential therapeutic implications for nanodrug delivery.

Overall, these findings establish the DNM1-N-cadherin axis as a critical regulator of EMT-associated ovarian cancer metastasis and suggest its potential as a biomarker for targeted nanodrug therapy. This research not only enhances our understanding of the mechanisms driving ovarian cancer but also opens new avenues for developing effective therapeutic strategies against this aggressive disease. The work entitled “Dynamin 1-mediated endocytic recycling of glycosylated N-cadherin sustains the plastic mesenchymal state to promote ovarian cancer metastasis ” was published on Protein & Cell (published on Apr. 09, 2025).
DOI：https://doi.org/10.1093/procel/pwaf019