Biology subjects

El-Habr, E. A.

Publications and source records attributed to El-Habr, E. A..

4 recordsLinked to original sources

bioRxiv2025

Immune Cells Infiltration of Patient Derived Glioblastoma Cells spheroids in Acoustic Levitation in Bulk Acoustic Wave devices

We describe an acoustofluidic device that allows scaffold-free structuration and culture of multi-cellular tumoroids composed of patient-derived glioblastoma cells only or in combination with non-cancerous cell. A PDMS chip of controlled height was created to allow acoustic levitation of cells using a 2 MHz transducer held on top of the chip. Cells are introduced into the chip through a dedicated inlet upstream of the resonant cavity. The specific design of the cavity together with the acoustic field allow the formation of tumoroids of cells in a precise and controlled manner within the levitation chamber. The acoustic and fluidic environment of the device was determined through experiments confronted with numerical simulations. The control of the flow within the chip was optimized to allow long-term culture of tumoroids and injection of cell culture media without disturbing the tumoroids in levitation. The tumoroids can be also structured, with sequential injections of the different cell types. Using microglia, we show that the acoustofluidic device allows the formation and culture in acoustic levitation of tumoroids mixing cancer cells with other cells populating the tumor as well as immune cell infiltration within the tumoroids. These results demonstrate the suitability of acoustofluidic levitation as an original 3D culture method adapted to the exploration of cancer growth at multiple levels.

bioengineering↗

bioRxiv2024

A unique malignant cell type per patient tumor is encoded in each cancer cell transcriptome.

Deciphering shared features between patients through unsupervised analyses of tumor single-cell transcriptomes is hindered by the predominant clustering of malignant cells based on the patients tumor of origin. In contrast, cancer-associated non-malignant cells within tumors cluster according to their somatic cell type (e.g. macrophage, fibroblast, astrocyte), regardless of the individual patient. We investigated the origin of this contrasting clustering behavior using computational analyses and novel data sampling techniques across 160 tumors representing 9 distinct cancer types. This led to the unexpected disclosing of tumor-specific malignant cell types. We demonstrate that tumor-driven malignant cell clustering is independent from technical or computational biases, nor is it reducible to defined gene sets with tumor-specific expression across all examined cancers. On the opposite, we unveil redundant information dispersed across the transcriptome that encodes a unique identity shared by the malignant cells within each tumor. Additionally, we found a similar genomic encoding for the identity of normal cell types. Finally, we demonstrate that malignant cell identities are maintained across space and over time, as are the identities of normal somatic cells types. These findings suggest the establishment of a distinct type of malignant cells within each tumor, robustly and diffusively encoded across the entire transcribed genome.

cancer biology↗

bioRxiv2022

Human glioblastoma cell motility depends on the activity of the cysteine metabolism enzyme 3-Mercaptopyruvate sulfurtransferase

Cancer cells in similar functional states are found in all glioblastoma, despite the genomic heterogeneity observed between and within these brain tumors. Metabolism being downstream of all signaling pathways regulating cell behaviors, we looked for metabolic weaknesses in link with motility, a key functional state for glioblastoma aggressiveness. A signature-driven data reduction approach highlighted motile cells present in thirty tumors from four independent single-cell transcriptomic datasets. Analyses integrating trajectory modeling disclosed, as characteristic of motile cells, enhanced oxidative stress coupled with mobilization of the cysteine metabolism enzyme 3-Mercaptopyruvate sulfurtransferase (MPST). The soundness of this prediction was verified using migration and invasion assays with patient-derived cells and tissue organoids. Pharmacological and genetic manipulations showed that enhanced ROS production and MPST activity are required for the cells motility. Biochemical assays indicated that MPST acts by protecting protein cysteine residues from dismal hyperoxidation. In vivo, MPST knockdown translated in reduced tumor burden, and a robust increase in mice survival. These results show that enhanced oxidative stress coupled with MPST mobilization plays a key role in glioblastoma cell motility.

cancer biology↗

bioRxiv2019

Capture at the single cell level of metabolic modules distinguishing aggressive and indolent glioblastoma cells

Glioblastoma cell ability to adapt their functioning to microenvironment changes is a source of the extensive intra-tumor heterogeneity characteristic of this devastating malignant brain tumor. A systemic view of the metabolic pathways underlying glioblastoma cell functioning states is lacking. We analyzed public single cell RNA-sequencing data from glioblastoma surgical resections, which offer the closest available view of tumor cell heterogeneity as encountered at the time of patients diagnosis. Unsupervised analyses revealed that information dispersed throughout the cell transcript repertoires encoded the identity of each tumor and masked information related to cell functioning states. Data reduction based on an experimentally-defined signature of transcription factors overcame this hurdle. It allowed cell grouping according to their tumorigenic potential, regardless of their tumor of origin. The approach relevance was validated using an independent dataset of glioblastoma tissue transcriptomes, patient-derived cell lines and orthotopic xenografts. Overexpression of genes coding for amino acid and lipid metabolism enzymes involved in anti-oxidative, energetic and cell membrane processes characterized cells with high tumorigenic potential. Modeling of their expression network highlighted the very long chain polyunsaturated fatty acid synthesis pathway at the core of the network. Expression of its most downstream enzymatic component, ELOVL2, was associated with worsened patient survival, and required for cell tumorigenic properties in vivo. Our results demonstrate the power of signature-driven analyses of single cell transcriptomes to obtain an integrated view of metabolic pathways at play within the heterogeneous cell landscape of patient tumors.

cancer biology↗