Biology subjects

Holaska, J. M.

Publications and source records attributed to Holaska, J. M..

3 recordsLinked to original sources

bioRxiv2025

Emerin expression stratification across breast cancer subtypes

Nuclear dysmorphism is a critical indicator of tumor aggressiveness, influencing cancer cell invasion and metastasis. Emerin, an integral nuclear envelope protein involved in nuclear architecture, is important for maintaining nuclear integrity. Our previous work demonstrated an inverse correlation between nuclear envelope-localized emerin expression and breast cancer aggressiveness. However, it failed to have the power to assess whether emerin loss correlates with cancer stage, grade, proliferation, or molecular phenotype. Here we analyzed emerin expression at the nuclear envelope across 243 breast cancer patient samples encompassing various tumor grades, stages, and molecular phenotypes. We found significantly reduced emerin expression in invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), and ductal carcinoma in situ (DCIS), compared to normal breast tissue. Notably, emerin loss correlated with advanced tumor stage, higher Ki-67 proliferation rates, elevated human epidermal growth factor receptor 2 (HER2) levels, and decreased estrogen receptor (ER) and progesterone receptor (PR) expression--markers associated with more aggressive breast cancers. Emerin expression was consistently reduced in triple-negative breast cancer (TNBC) and other receptor-negative subtypes, underscoring its potential role in tumor dedifferentiation and progression. These findings highlight emerin as a promising prognostic biomarker and therapeutic target for aggressive breast cancer subtypes.

cancer biology↗

bioRxiv2025

Development of Emerin mRNA Lipid Nanoparticles to Rescue Myogenic Differentiation

Emery-Dreifuss muscular dystrophy 1 (EDMD1) arises from mutations in EMD. Most EDMD1 patients lack detectable emerin expression. They experience symptoms such as skeletal muscle wasting, joint contractures, and cardiac conduction defects. Currently, physicians rely on treating patient symptoms, without addressing the underlying cause - lack of functional emerin protein. Thus, there is a need for therapeutic approaches that restore emerin protein expression to improve patient outcomes. One way would be to deliver emerin mRNA or protein directly to affected tissues to restore tissue homeostasis. Here, we evaluated the utility of lipid nanoparticles (LNPs) to deliver emerin mRNA to diseased cells. LNPs have been studied for decades and have recently been used clinically for vaccination and treatment of myriad of diseases. Here, we show treatment of emerin-null myogenic progenitors with LNPs encapsulating emerin mRNA causes robust emerin protein expression that persists for at least 4 days. Treatment of differentiating emerin-null myogenic progenitors with 2.5 pg/cell emerin LNPs significantly improved their differentiation. Toxicity profiling of emerin mRNA LNP (EMD-LNP) dosing shows little toxicity at the effective dose. These data support the potential use of EMD-LNPs as a viable treatment option and establishes its utility for studying EDMD pathology.

cell biology↗

bioRxiv2024

Emerin deficiency drives MCF7 cells to an invasive phenotype

During metastasis, cancer cells traverse the vasculature by squeezing through very small gaps in the endothelium. Thus, nuclei in metastatic cancer cells must become more malleable to move through these gaps. Our lab showed invasive breast cancer cells have 50% less emerin protein resulting in smaller, misshapen nuclei, and higher metastasis rates than non-cancerous controls. Thus, emerin deficiency was predicted to cause increased nuclear compliance, cell migration, and metastasis. We tested this hypothesis by downregulating emerin in noninvasive MCF7 cells and found emerin knockdown causes smaller, dysmorphic nuclei, resulting in increased impeded cell migration. Emerin reduction in invasive breast cancer cells showed similar results. Supporting the clinical relevance of emerin reduction in cancer progression, our analysis of 192 breast cancer patient samples showed emerin expression inversely correlates with cancer invasiveness. We conclude emerin loss is an important driver of invasive transformation and has utility as a biomarker for tumor progression.

cancer biology↗