Protein DNM1 identified as key regulator in ovarian cancer metastasis

Ovarian cancer remains the leading cause of death among cancers affecting the female reproductive system, largely because current treatments are not effective once the cancer has spread (metastasized) beyond the ovaries.

A recent study has identified a critical factor driving this metastasis, offering promising new directions for targeted treatment strategies. The team's findings appear inProtein and Celland are featured as the journal's cover article, highlighting the significance of this work.

The work was led by Professor Alice Wong, Interim Director of the School of Biological Sciences at The University of Hong Kong (HKU).

The researchers focused on a biological process called epithelial-to-mesenchymal transition (EMT). This process makes cancer cells more flexible and able to move, which helps them spread and makes the disease more challenging to treat. Scientists have struggled to find a part of this process that can be targeted with drugs.

To tackle this challenge, the team employed a master regulator (MR) algorithm to analyze regulatory networks of gene and protein interactions. By analyzing data from over 8,000 patient samples across 20 cancer types in The Cancer Genome Atlas (TCGA), they identified dynamin 1 (DNM1) as a novel, non-transcriptional regulator of EMT. Unlike traditional regulators that control gene expression and are difficult to target, DNM1 acts through alternative cellular mechanisms, presenting novel treatment opportunities.

Notably, higher levels of DNM1 were found in patients with advanced disease and mesenchymal subtypes, and these elevated levels were associated with worse survival outcomes. This discovery suggests that targeting DNM1 could be a valuable strategy to improve outcomes for these patients.

Experimental insights

In cell-based experiments, inhibiting DNM1 in aggressive ovarian cancer cells significantly reduced their ability to migrate. It also lowered levels of N-cadherin, a key EMT marker linked to aggressive cancer behavior. On the other hand, increasing DNM1 in non-metastatic cells made them more invasive and increased N-cadherin levels. Animal studies also confirmed that reducing DNM1 led to less cancer spread within the abdomen, reinforcing DNM1's role in promoting metastasis

The researchers discovered that DNM1 works by helping cancer cells take in (endocytose) and reuse (recycle) N-cadherin, a process that maintains cell polarity and enables migration. These functions are crucial for allowing cancer cells to become more mobile and invasive, contributing to their spread throughout the body.

Notably, the integration of ATAC-seq and RNA-seq analyses showed that non-metastatic cells exhibited higher expression of the glycosyltransferase gene B3GALT1, potentially inhibiting EMT by reducing N-cadherin recycling. Intriguingly, metastatic cells with high DNM1 were more efficient at taking up nanoparticle-based drugs, suggesting a potential advantage for targeted nanomedicine.

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 the understanding of the mechanisms driving ovarian cancer but also opens new avenues for developing effective therapeutic strategies against this aggressive disease.

This article was originally published on MedicalXpress Breaking News-and-Events.