Biology subjects

Shohet, J.

Publications and source records attributed to Shohet, J..

4 recordsLinked to original sources

bioRxiv2024

Investigation of cell mechanics and migration on DDR2-expressing neuroblastoma cell line

Neuroblastoma is a devastating disease accounting for ~15% of all childhood cancer deaths. Collagen content and fiber association within the tumor stroma influence tumor progression and metastasis. High expression levels of collagen receptor kinase, Discoidin domain receptor II (DDR2), are associated with poor survival of neuroblastoma patients. Additionally, cancer cells generate and sustain mechanical forces within their enviroment as a part of their normal physiology. Despite this, whether collagen activated DDR2 signaling dysregulate these migration forces is still elusive. To address these questions, a shRNA DDR2 knockdown neuroblastoma cell line (SH-SY5Y) was engineered to evaluate the consequence of DDR2 on cellular mechanics. Atomic force microscopy and traction force microscopy were utlizing to unveil the biophysical altercations. DDR2 down-regulation was found to significantly reduce proliferation, cell stiffness, and cellular elongation. Aditionally, DDR2 down-regulated cells had decreased traction forces when plated on collagen coated elastic substrates. Together, these results highlight the important role that DDR2 has in reducing migration mechanics in neuroblastoma and might be a promising target for future therapies.

cell biology↗

bioRxiv2023

The roles of DDR2 and substrate stiffness on cancer cell transcriptome and proliferation

The interactions between cancer cells and the ECM regulate carcinogenesis. The collagen receptor kinase DDR2 is dysregulated in certain cancer cells, but its precise role in these malignancies remains unclear. In this study, we perform RNA-seq to determine how DDR2 and the biomechanical environment regulate cancer cell behaviors. We show that DDR2 knockdown in SH-SY5Y neuroblastoma cells inhibits proliferation and promotes senescence by regulating relevant genes. Increasing substrate stiffness reduces proliferation and promotes cell spreading but does not change senescence or transcriptome. Furthermore, DDR2 knockdown modulates cellular responses to substrate stiffness changes, unraveling a crosstalk between DDR2 and mechanosensing. These findings indicate DDR2 and ECM biomechanics regulate cancer cell behavior through distinct mechanisms, providing new mechanistic insights of cancer progression.

biochemistry↗

bioRxiv2020

KDM6B promotes oncogenic CDK4/6-pRB-E2F pathway via maintaining enhancer activation in high-risk neuroblastoma

The H3K27me2/me3 histone demethylase KDM6B is over-expressed in neuroblastoma and is essential to neuroblastoma cell survival. While the KDM6B inhibitor, GSK-J4, has shown activity in in vitro and in vivo preclinical models, the mechanism of action remains poorly defined. We demonstrate that genetic and pharmacologic inhibition of KDM6B downregulates the pRB-E2F transcriptome and MYCN expression. Chemical genetic analyses show that high expression of the E2F transcriptome is positively correlated with sensitivity of cancer cells to GSK-J4. Mechanistically, inhibition of KDM6B activity 1) reduces the chromatin accessibility of E2F target genes and MYCN, 2) selectively leads to an increase of H3K27me3 but a decrease of the enhancer mark H3K4me1 at the CTCF and BORIS binding sites, which may, consequently, disrupt the long-range chromatin interaction of MYCN and E2F target genes, and 3) phenocopies the transcriptome induced by the specific CDK4/6 inhibitor palbociclib. Overexpression of CDK4/6 or Rb1 knockout confers neuroblastoma cell resistance to both palbociclib and GSK-J4. A gene signature targeted by KDM6B inhibition is associated with poor survival of patients with neuroblastoma regardless of the MYCN status. These data indicate that KDM6B activity promotes an oncogenic CDK4/6-pRB-E2F pathway in neuroblastoma cells via H3K27me3-dependent enhancer-promoter interactions, providing a rationale to target KDM6B for high-risk neuroblastoma.

cancer biology↗

bioRxiv2018

Circulating microRNA biomarkers for metastatic disease in neuroblastoma patients

In this study, the circulating miRNome from diagnostic neuroblastoma serum was assessed for identification of non-invasive biomarkers with potential in monitoring metastatic disease. After determining the circulating neuroblastoma miRNome, 743 miRNAs were screened in two independent cohorts of 131 and 54 patients. Evaluation of serum miRNA variance in a model testing for tumor stage, MYCN status, age at diagnosis and overall survival, revealed tumor stage as the most significant factor impacting miRNA abundance in neuroblastoma serum. Differential expression analysis between patients with metastatic and localized disease revealed 9 miRNAs strongly associated with metastatic stage 4 disease in both patient cohorts. Increasing levels of these miRNAs were also observed in serum from xenografted mice bearing human neuroblastoma tumors. Moreover, murine serum miRNA levels were strongly associated with tumor volume, suggesting this miRNA signature may be applied to monitor disease burden.

cancer biology↗