8 research outputs found
EHD2 Promotes Store-Operated Calcium Entry (SOCE) and Cellular Migration in Ovarian Cancer Cells
Ovarian cancer (OC) ranks as the 5th most common cause of cancer deaths of women, reflecting late diagnoses and lack of targeted therapies. EHD2, a member of the Eps15 homology (EH) domain containing (EHD) proteins family, regulates cell surface expression of Orai1, the mediator of store-operated calcium entry (SOCE) in breast cancer. Disrupting the EHD2-Orai1 axis in OC could provide novel targeted therapies against metastatic disease.https://digitalcommons.unmc.edu/surp2023/1002/thumbnail.jp
Comparative Immunohistochemical Analysis of EHD1 Expression in Adjacent, Metastatic, and Normal Thyroid Tissue
The discovery of prognostic biomarkers plays a crucial role in enhancing the treatment and care of individuals with differentiated thyroid cancer (DTC) who are at risk of disease progression. A significant breakthrough came with earlier research, which revealed higher levels of the EHD1 protein in papillary DTC when compared to the surrounding healthy tissue. This exciting finding served as the driving force behind the initiation of a more extensive investigation aimed at validating EHD1 as a potential biomarker and exploring its connection with clinical outcomes. By unraveling the potential implications of EHD1 in DTC cases, this study holds the promise of advancing our understanding and approach to managing this type of cancer effectively.https://digitalcommons.unmc.edu/surp2023/1001/thumbnail.jp
EHD1 is Required for IGF-1R-mediated Oncogenic Signaling in Ewing Sarcoma
Background and Significance: Ewing Sarcoma (EWS) is the second most common malignant bone tumor of children and adolescents. Patients with metastatic or recurrent disease have very poor outcomes. The receptor tyrosine kinase(RTK) insulin-like-growth-factor-1-receptor (IGF-1R) is upregulated in 93% of EWS patients with anti-IGF-1R antibodies and kinase inhibitors in clinical studies. However, with only ~10% of patients achieving objective responses, delineation of novel pathways that facilitate IGF-1R-driven oncogenesis in EWS could provide avenues for more effective therapy. The RTK levels and compartmentalization at the cell surface determine their access to growth factors, thus dictating the downstream oncogenic signaling. Our lab has demonstrated that EPS15-homology-domain-containing-protein-1 (EHD1) regulates traffic of cell surface receptors, including RTKs. We observed high frequency (67%) of EHD1 overexpression in 266 primary EWS patient tumor tissues, and Kaplan-Meier survival analysis of publicly available mRNA expression data showed that high EHD1 expression was associated with shorter patient survival.
Objective/Question: This study aims to comprehend the underlying role of EHD1 in EWS oncogenesis.
Experimental design and Results: In both dox-inducible EHD1-shRNA knockdown and EHD1-CRISPR-Cas9-knockout (KO) EWS cell line models(TC71, A673, and SKES1), we observed a significant impairment of in vitro oncogenic properties namely, cell proliferation, migration, invasion, soft-agar colony formation, and tumor-sphere formation, and the phenotypes were restored upon mouse-EHD1 rescue. Furthermore, by orthotopically implanting TC71 cells in the tibia of nude mice(xenograft model), we demonstrated a significant reduction in tumor size upon EHD1-depletion. Using a phospho-RTK profiling antibody array, we found reduced phospho-IGF-1R levels upon EHD1-KD, identifying IGF-1R as a potential target of regulation by EHD1. EHD1-KO reduced surface IGF-1R levels under steady-state and ligand-free conditions in EWS cells. IGF-1R and EHD1 were also found to colocalize intracellularly and co-immunoprecipitate after IGF-1 stimulation. Notably, EHD1-KO impaired the IGF-1R-mediated activation of downstream AKT and MAPK pathways. Mechanistically, EHD1 was shown to regulate traffic of newly synthesized IGF-1R and recycled pools from the Golgi to the cell surface, and in absence of EHD1, intracellular IGF-1R was shunted to the lysosome resulting in degradation. Finally, by dual targeting of EHD1 (genetic depletion) and IGF-1R (small-molecule-inhibitor Linsitinib), we observed an additive effect on inhibition of EWS cell proliferation and migration and upregulation of apoptosis.
Conclusions: Our studies indicate a novel regulatory pathway of EHD1 requirement in IGF-1R cell surface display and sustaining IGF-1R-mediated oncogenesis in EWS. This highlights the prospects of therapeutic co-targeting of EHD1 and IGF-1R, thus enhancing IGF-1R targeted therapies in EWS.https://digitalcommons.unmc.edu/chri_forum/1040/thumbnail.jp
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Increasing adherence and collecting symptom-specific biometric signals in remote monitoring of heart failure patients: a randomized controlled trial.
OBJECTIVES: Mobile health (mHealth) regimens can improve health through the continuous monitoring of biometric parameters paired with appropriate interventions. However, adherence to monitoring tends to decay over time. Our randomized controlled trial sought to determine: (1) if a mobile app with gamification and financial incentives significantly increases adherence to mHealth monitoring in a population of heart failure patients; and (2) if activity data correlate with disease-specific symptoms. MATERIALS AND METHODS: We recruited individuals with heart failure into a prospective 180-day monitoring study with 3 arms. All 3 arms included monitoring with a connected weight scale and an activity tracker. The second arm included an additional mobile app with gamification, and the third arm included the mobile app and a financial incentive awarded based on adherence to mobile monitoring. RESULTS: We recruited 111 heart failure patients into the study. We found that the arm including the financial incentive led to significantly higher adherence to activity tracker (95% vs 72.2%, P = .01) and weight (87.5% vs 69.4%, P = .002) monitoring compared to the arm that included the monitoring devices alone. Furthermore, we found a significant correlation between daily steps and daily symptom severity. DISCUSSION AND CONCLUSION: Our findings indicate that mobile apps with added engagement features can be useful tools for improving adherence over time and may thus increase the impact of mHealth-driven interventions. Additionally, activity tracker data can provide passive monitoring of disease burden that may be used to predict future events
Computer assisted classification framework for prediction of acute lymphoblastic and acute myeloblastic leukemia
EHD1-dependent traffic of IGF-1 receptor to the cell surface is essential for Ewing sarcoma tumorigenesis and metastasis
Abstract Overexpression of the EPS15 Homology Domain containing 1 (EHD1) protein has been linked to tumorigenesis but whether its core function as a regulator of intracellular traffic of cell surface receptors plays a role in oncogenesis remains unknown. We establish that EHD1 is overexpressed in Ewing sarcoma (EWS), with high EHD1 mRNA expression specifying shorter patient survival. ShRNA-knockdown and CRISPR-knockout with mouse Ehd1 rescue established a requirement of EHD1 for tumorigenesis and metastasis. RTK antibody arrays identified IGF-1R as a target of EHD1 regulation in EWS. Mechanistically, we demonstrate a requirement of EHD1 for endocytic recycling and Golgi to plasma membrane traffic of IGF-1R to maintain its surface expression and downstream signaling. Conversely, EHD1 overexpression-dependent exaggerated oncogenic traits require IGF-1R expression and kinase activity. Our findings define the RTK traffic regulation as a proximal mechanism of EHD1 overexpression-dependent oncogenesis that impinges on IGF-1R in EWS, supporting the potential of IGF-1R and EHD1 co-targeting
GD2 and its biosynthetic enzyme GD3 synthase promote tumorigenesis in prostate cancer by regulating cancer stem cell behavior
Abstract While better management of loco-regional prostate cancer (PC) has greatly improved survival, advanced PC remains a major cause of cancer deaths. Identification of novel targetable pathways that contribute to tumor progression in PC could open new therapeutic options. The di-ganglioside GD2 is a target of FDA-approved antibody therapies in neuroblastoma, but the role of GD2 in PC is unexplored. Here, we show that GD2 is expressed in a small subpopulation of PC cells in a subset of patients and a higher proportion of metastatic tumors. Variable levels of cell surface GD2 expression were seen on many PC cell lines, and the expression was highly upregulated by experimental induction of lineage progression or enzalutamide resistance in CRPC cell models. GD2high cell fraction was enriched upon growth of PC cells as tumorspheres and GD2high fraction was enriched in tumorsphere-forming ability. CRISPR-Cas9 knockout (KO) of the rate-limiting GD2 biosynthetic enzyme GD3 Synthase (GD3S) in GD2high CRPC cell models markedly impaired the in vitro oncogenic traits and growth as bone-implanted xenograft tumors and reduced the cancer stem cell and epithelial-mesenchymal transition marker expression. Our results support the potential role of GD3S and its product GD2 in promoting PC tumorigenesis by maintaining cancer stem cells and suggest the potential for GD2 targeting in advanced PC