Diagram illustrating how DNM1 regulates EMT and metastasis. High levels of DNM1 enhance N-cadherin endocytic recycling, leading to increased metastasis and greater potential for nanotherapy. In contrast, elevated B3GALT1 levels reduce N-cadherin expression in non-metastatic tumors, which limits their metastatic ability. Image adapted from BioArt.
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 (metastasised) beyond the ovaries. A recent study led by Professor Alice WONG, Interim Director from the HKU School of Biological Sciences of The University of Hong Kong (HKU), has identified a critical factor driving this metastasis, offering promising new directions for targeted treatment strategies. The team’s findings have just been published in Protein and Cell.
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 harder 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 analyse regulatory networks of gene and protein interactions. By analysing 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 behaviour. 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.
Conclusion and Future Directions
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.
For those eager to explore this fascinating research further, the full details can be found in the journal Protein and Cell under the title ‘Dynamin 1-mediated endocytic recycling of glycosylated N-cadherin sustains the plastic mesenchymal state to promote ovarian cancer metastasis’ .
香港大學（港大）生物科學學院暫任院長黃思齊教授領導的研究團隊，確認了一種能驅動卵巢癌擴散的因子，為開發新型治療標靶帶來了希望。研究成果已刊於《蛋白質與細胞》（Protein and Cell）。
研究背景
卵巢癌是婦科癌症中死亡率最高的類型，大多數患者確診時，癌細胞已擴散至腹膜。晚期患者的五年存活率不足 25%。其「上皮－間質轉化」（EMT，epithelial-to-mesenchymal transition）是癌細胞更容易擴散至腹膜並加重病情的關鍵。然而，醫學界一直未有找到促進此過程的驅動因子。
研究成果
港大生物科學學院暫任院長黃思齊教授及團隊，採用了「主調控因子演算法」（Master Regulator Algorithm），分析來自 8000 名患者、包括 20 種不同癌症類型的基因組圖譜數據，識別出動力蛋白 1（DNM1/ Dynamin 1）是一種新型非基因轉錄的 EMT 主調控因子。
其與傳統難以靶向的基因轉錄的調控因子不同，乃是通過其他細胞機制發揮作用，這為治療提供了新的機會。此外，它在晚期和「間質亞型」的患者中，水平顯著升高，與患者較快的病情惡化速度以及較短的復發後存活時間有關。
體外實驗顯示，抑制 DNM1 可以顯著降低卵巢癌細胞的侵略性及擴散力，同時讓 EMT 關鍵標記 N- 鈣黏蛋白（N-cadherin）表現下降。相反，在非轉移性細胞中增加 DNM1 的表達則會誘導其侵略性的特徵，並提高 N- 鈣黏蛋白的水平。活體研究亦與這些體外實驗結果一致。
此外，DNM1 可促進 N- 鈣黏蛋白的內吞和回收。團隊發現，非轉移性細胞中糖基轉移酶基因 B3GALT1 的表達增加，可能減少 N- 鈣黏蛋白回收，從而抑制 EMT。而 DNM1 水平較高的轉移性細胞，在吸收納米顆粒的藥物時效率更高。
這些發現，確立了 DNM1- N-鈣 黏蛋白軸，作為卵巢癌 EMT 相關轉移的關鍵調控因子，並有潛力成為靶向納米藥物的生物標記物。
研究團隊
論文共同通訊作者為港大生物科學學院暫任院長黃思齊教授、港大生物科學學院杜潔欣博士。