Biology subjects

Rozen, E. J.

Publications and source records attributed to Rozen, E. J..

3 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

Phosphorylation of MYCN and MAX by PAK family kinases is a novel tumor-suppressor mechanism in neuroblastoma with potential therapeutic implications.

High-risk Neuroblastoma (HR-NB) is a very aggressive pediatric cancer, responsible of over 15% of all childhood cancer-associated deaths. Despite very aggressive multimodal interventions, less than 50% of HR-NB patients survive, exhibiting serious long-term sequelae from therapy. Therefore, more efficient, and less toxic interventions are urgently needed. Genomic amplification of the MYCN gene is observed in about 50% of all HR-NB cases, and is the most reliable genomic hallmark associated to a bad prognosis. c-MYC is highly expressed in a significant amount of the remaining (non-MYCN-amplified) HR-NB cases. Here, we investigated an endogenous mechanism mediated by the PAK2 kinase and known to phosphorylate and suppress c-MYC transcriptional activity. We uncovered that PAK2 can also phosphorylate MYCN and its obligate transcriptional partner MAX in two conserved Ser/Thr residues, disrupting MYCN:MAX interaction, transcription, and neuroblastoma cell proliferation. We further provide evidence for a potential mechanism by which PAK kinase activity is blunted in MYCN-amplified neuroblastoma tumors and propose an innovative strategy to circumvent such signaling impairment and potentially suppress HR-NB tumor growth.

cancer biology↗

bioRxiv2023

A novel druggable DYRK3/CAMKV signaling module for Neuroblastoma tumor growth inhibition.

High-risk Neuroblastoma is a very aggressive and deadly pediatric cancer, accounting for over 15% of all childhood cancer mortality. Therefore, novel therapeutic strategies for the treatment of neuroblastoma are urgently sought for. Here, we identified the DYRK3 kinase as a critical mediator of neuroblastoma cell proliferation and in vivo tumor growth. Our data suggest a role for DYRK3 as a regulator of the neuroblastoma-specific protein CAMKV, which is also required for neuroblastoma cell proliferation. We show that CAMKV is phosphorylated by DYRK3, and that inhibition of DYRK3 kinase activity induces CAMKV aggregation, probably mediated by its highly disordered C-terminal half. Importantly, we provide evidence that the DYRK3/CAMKV signaling module could play an important role in the regulation of the mitotic spindle during cell division, supporting the idea that inhibition of DYRK3 and/or CAMKV in neuroblastoma cells could constitute an innovative and highly specific intervention to fight against this dreadful pediatric cancer.

cancer biology↗