Biology subjects

Abu Rmaileh, A.

Publications and source records attributed to Abu Rmaileh, A..

4 recordsLinked to original sources

bioRxiv2026

Dihydropyrimidines sustain aggressive cancer states by stabilizing DPYSL2

Cancer cell states are governed by coordinated signaling and metabolic networks, yet the mechanisms coupling metabolic activity to oncogenic signaling remain poorly understood. Here, we identify dihydropyrimidines (DHPs), metabolites generated during pyrimidine catabolism, as "signaling metabolites" that sustain aggressive cancer cell states. Depletion of DHPs, either by knockout of the pyrimidine catabolic enzyme DPYD or by expression of the DHP-degrading enzyme DPYS, suppressed STAT3 signaling and attenuated mesenchymal and inflammatory transcriptional programs. Mechanistically, DHPs stabilized DPYSL2, a JAK1-interacting adaptor protein required for efficient STAT3 activation. Structural modeling and thermal stability analyses further support a direct interaction between DHPs and DPYSL2. Accordingly, high DPYD expression was associated with EMT, inflammatory signaling, and poor-prognosis breast cancer subtypes across patient cohorts. Ultimately, our findings establish pyrimidine catabolism as a direct regulator of signaling competence and identify DHPs as signaling-active metabolites that couple cellular metabolic state to oncogenic transcriptional programs and mesenchymal identity.

cancer biology↗

bioRxiv2023

GENI: a web server to identify gene set enrichments in tumor samples

The Cancer Genome Atlas (TCGA) and other projects provide informative tumor-associated genomic data for the broad research community. Hence, several useful web-based tools have been generated to ease non-expert users with the analysis and characterization of a specific gene behavior in selected tumors. However, none of the existing tools offer the user the means to evaluate the expression profile of a given gene in the context of the whole transcriptome. Currently, such analyses require prior bioinformatic knowledge and expertise. Therefore, we developed GENI (Gene ENrichment Identifier) as a fast, user-friendly tool to analyze the TCGA expression data for gene set enrichments. GENI analyzes large-scale tumor-associated gene expression datasets and evaluates biological relevance, thus offering researchers a simplified means to analyze cancer patient-derived data. Availability and implementationGENI is a freely available fast web-based tool developed using the R programming language. It is accessible via the URL: https://yoavshaul-lab.shinyapps.io/gsea-geni/. The complete script can be found at https://github.com/ArataHayashi/GENI-Gene-ENrichment-Identifier.

bioinformatics↗

bioRxiv2021

Dihydropyrimidinase-like 2 (DPYSL2) regulates breast cancer migration via a JAK/STAT3/vimentin axis

The intricate neuronal wiring during development requires cytoskeletal reorganization orchestrated by signaling cues. Considering that cytoskeletal remodeling is a hallmark of cell migration, we inquired whether metastatic cancer cells exploit the axon guidance proteins to migrate. Indeed, in breast cancer patients, we found a significant correlation between the mesenchymal markers and the expression of dihydropyrimidinase-like 2 (DPYSL2), a regulator of cytoskeletal dynamics in growing axons. Strikingly, DPYSL2 knockout in mesenchymal-like cells profoundly inhibited cell migration, invasion, stemness features, tumor growth rate, and metastasis. Next, we aimed to decode the molecular mechanism underlying this phenomenon and revealed an interaction between DPYSL2 and Janus kinase 1 (JAK1). This binding is crucial for triggering signal transducer and activator of transcription 3 (STAT3) and subsequently expressing vimentin, the pro-migratory intermediate filament. Collectively, we identified DPYSL2 as a molecular link between oncogenic signaling pathways and cytoskeletal reorganization in migrating breast cancer cells. Statement of significanceThis study shows that the axon guidance adaptor protein DPYSL2 is essential for promoting breast cancer migration. Specifically, this protein interacts with JAK1 to govern STAT3 signaling and subsequently vimentin expression.

cancer biology↗

bioRxiv2019

Glutathione Peroxidase 8 (GPX8)-IL6 axis is essential in maintaining breast cancer mesenchymal stem-like state and aggressive phenotype

Metabolic reprogramming as a downstream result of oncogenic signaling pathways has been described as a hallmark of cancer. Here, we describe a reverse scenario in which a metabolic enzyme regulates cancer cell behavior by triggering a signaling pathway. We find that glutathione peroxidase 8 (GPX8), a poorly characterized redox enzyme that resides in the endoplasmic reticulum, is upregulated during the epithelial-to-mesenchymal (EMT) program in HMLE and A549 cells. In cancer patients, high tumor levels of GPX8 correlate with mesenchymal markers and poor patient outcome. Strikingly, GPX8 knockout in mesenchymal-like cells results in an epithelial-like morphology, downregulation of EMT characteristics, loss of cancer stemness features, and impeded tumor initiation in mice. We determine the mechanism governing this reduction in cancer aggressiveness is through the repression of crucial autocrine factors, in particular, interleukin-6 (IL-6). Specifically, GPX8 knockout impairs IL-6-driven activation of the JAK-STAT3 signaling pathway, a critical regulator of a cancer-aggressive state. Altogether, we uncover the GPX8-IL-6 axis as a novel metabolic-inflammatory pathway that acts as a robust EMT activator and program to induce aggressive cancer cell characteristics.

cancer biology↗