Ovarian cancer remains one of the most lethal malignancies impacting women worldwide, primarily due to its insidious capacity to metastasize beyond the ovaries before clinical detection. Despite advances in surgical techniques and chemotherapeutic regimens, survival rates have stagnated, underscoring an urgent need to unravel the molecular underpinnings that fuel ovarian cancer dissemination. In a groundbreaking study spearheaded by Professor Alice Wong at The University of Hong Kong, researchers have elucidated a pivotal mechanism governing ovarian cancer metastasis, spotlighting dynamin 1 (DNM1) as a critical regulator of the epithelial-to-mesenchymal transition (EMT). This discovery not only deepens our comprehension of cancer biology but also opens new therapeutic avenues in an arena fraught with complexity and clinical challenges.
EMT is a cellular program whereby epithelial cells relinquish their tight junctions and intrinsic polarity to acquire mesenchymal traits—traits that endow cancer cells with increased motility, invasiveness, and resistance to apoptosis. This phenotypic plasticity is a fundamental driver of metastasis, yet targeting EMT therapeutically has been confounded by its intricate regulation and the transcription factors traditionally involved, many of which lack druggable features. Professor Wong’s team circumvented this obstacle by applying an innovative master regulator (MR) algorithm, capable of dissecting vast gene-protein interaction networks to reveal non-canonical regulatory molecules within cancer cells. Analyzing over 8,000 patient samples across 20 types of malignancies curated by The Cancer Genome Atlas (TCGA), they pinpointed DNM1 as a novel, non-transcriptional modulator orchestrating EMT dynamics.
Dynamin 1, historically studied for its canonical role in endocytosis, emerged in this study as a linchpin controlling the turnover and recycling of N-cadherin, a key adhesion molecule and hallmark of the mesenchymal phenotype. Elevated DNM1 expression correlated strongly with advanced disease stages and mesenchymal tumor subtypes, and, strikingly, higher DNM1 levels were prognostic of poorer survival outcomes. This inverse relationship between DNM1 expression and patient prognosis emphasizes the biological and clinical significance of its role, differentiating it from traditional EMT regulators and underscoring its potential as a biomarker and therapeutic target.
To experimentally substantiate these computational insights, the researchers examined the functional consequences of modulating DNM1 in various ovarian cancer cell lines. Suppression of DNM1 drastically diminished the cells’ migratory ability, simultaneously curtailing N-cadherin levels. Conversely, ectopic overexpression of DNM1 in non-metastatic cells induced a marked increase in invasiveness alongside elevated N-cadherin expression. This bidirectional manipulation elucidated the causative role of DNM1 in promoting a mesenchymal, motile phenotype crucial for metastasis. Complementary in vivo studies employing murine models further validated that reduced DNM1 expression suppressed intra-abdominal dissemination of ovarian cancer cells, reinforcing the protein’s centrality in metastatic progression.
Mechanistically, the study unveiled that DNM1 facilitates the endocytic recycling of glycosylated N-cadherin, a process vital for sustaining cell polarity and directed migration. Unlike transcription factors governing EMT gene expression, DNM1 operates at the post-translational level, manipulating protein trafficking pathways to maintain mesenchymal cellular states conducive to metastasis. By enhancing N-cadherin recycling, DNM1 preserves the plasticity and adaptability of cancer cells, enabling them to navigate complex microenvironments and breach biological barriers with heightened efficiency.
Complementary genomic approaches integrating ATAC-seq and RNA-seq illuminated a contrasting molecular signature in non-metastatic cells, which exhibited higher expression of B3GALT1, a glycosyltransferase implicated in inhibiting EMT progression. B3GALT1 appears to diminish N-cadherin recycling, thereby abrogating its surface expression and limiting metastatic competencies. This yin-yang interplay between DNM1 and B3GALT1 portrays a finely tuned regulatory balance influencing ovarian cancer’s metastatic trajectory and suggests that restoring B3GALT1 activity might be a viable strategy to restrain EMT and tumor dissemination.
Intriguingly, the investigation also revealed a serendipitous linkage between DNM1 expression and nanomedicine responsiveness. Metastatic ovarian cancer cells with elevated DNM1 were found to internalize nanoparticle-based therapeutics more efficiently, implying that DNM1’s role in endocytic pathways could be harnessed to augment targeted drug delivery. This insight elevates the DNM1-N-cadherin axis beyond a mere mechanistic curiosity, positioning it as a dual-purpose target with both anti-metastatic and drug delivery-enhancing potential.
Taken together, Professor Wong’s research delineates a novel molecular axis—DNM1-mediated endocytic recycling of N-cadherin—that sustains the mesenchymal phenotype fundamental to ovarian cancer metastasis. The identification of DNM1 as a master regulator operating through membrane trafficking, rather than transcriptional reprogramming, represents a paradigm shift for the field. This mechanism not only provides a fresh perspective on tumor biology but also charts a feasible path for therapeutic interventions aimed at halting or even reversing metastatic progression in ovarian cancer patients.
Beyond deepening biological understanding, these findings raise tantalizing prospects for clinical translation. Therapeutic strategies designed to inhibit DNM1 function could stymie cancer cell motility and dissemination, thereby improving patient outcomes. Moreover, the enhanced uptake of nanodrugs by DNM1-high metastatic cells suggests that nanotherapy platforms may be optimized or personalized based on DNM1 expression profiles, increasing drug efficacy while potentially reducing systemic toxicity. Such precision medicine approaches could radically transform the management of advanced ovarian cancer, a domain historically mired in therapeutic futility.
Further research exploring small-molecule inhibitors or biologics targeting DNM1, along with the development of diagnostic tools quantifying its expression, will be critical next steps. Additionally, investigating the interplay between DNM1, glycosylation enzymes like B3GALT1, and other endocytic regulators could unravel additional vulnerabilities exploitable for intervention. Understanding how DNM1’s activity integrates with the tumor microenvironment and standard chemotherapies will also be essential to effectively translate these findings into clinical practice.
In summary, the work from The University of Hong Kong heralds a new frontier in ovarian cancer research, revealing how a previously underappreciated protein governs the plasticity and metastatic propensity of tumor cells through a non-transcriptional mechanism. This advances the paradigm of cancer metastasis, shifting focus to the dynamic control of protein trafficking and receptor recycling as fertile ground for scientific exploration and drug development. It is a clarion call for heightened investigation into the molecular choreography that fuels cancer aggression, with hopes for more effective and durable treatments on the horizon.
Subject of Research: Cells
Article Title: Dynamin 1-mediated endocytic recycling of glycosylated N-cadherin sustains the plastic mesenchymal state to promote ovarian cancer metastasis
News Publication Date: 10-Apr-2025
Web References: http://dx.doi.org/10.1093/procel/pwaf019
Image Credits: The University of Hong Kong
Keywords: Health and medicine, Life sciences
