Biology subjects

Saurty-Seerunghen, M. S.

Publications and source records attributed to Saurty-Seerunghen, M. S..

5 recordsLinked to original sources

bioRxiv2026

Targeted sequencing of mutations via RNA-templated gap filling of oligonucleotides for single-cell RNA-seq

We describe a method for targeted sequencing of expressed mutations in single cells. The approach exploits the reverse transcriptase and nick translation activities of the Bst DNA polymerase (Full Length) from Bacillus stearothermophilus (BstFL) to perform an RNA-templated gap filling and ligation between flanking probes. Integrated with probe-based single cell RNAseq workflows, it enables simultaneous whole transcriptomic and multiplexed mutation profiling from the same cell, overcoming key limitations of mutation detection in existing scRNA-seq approaches.

molecular biology↗

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↗

bioRxiv2024

Nicotinamide Metabolism Reprogramming Drives Reversible Senescence of Glioblastoma Cells

Recent studies show that metabolites, beyond their metabolic roles, can induce significant changes in cell behavior. Herein, we investigate the non-canonical role of nicotinamide (vitamin B3) on glioblastoma (GB) cell behavior. Nicotinamide induced senescence in GB cells, characterized by reduced proliferation, chromatin reorganization, increased DNA damage, enhanced beta-galactosidase activity, and decreased Lamin B1 expression. Nicotinamide-induced senescence was accompanied by an unexpected reprogramming of its metabolism, marked by simultaneous downregulated transcription of NNMT (nicotinamide N-methyltransferase) and NAMPT (nicotinamide phosphoribosyl-transferase). Nicotinamide effects on GB cells were mediated by decreased levels of SOX2. Consistently, analyses of patients single cell transcriptome datasets showed that GB cells with low NNMT and NAMPT expression levels were enriched in gene modules related to senescence. Remarkably, senescent GB cells retained tumor-forming ability in vivo, albeit to a lesser extent compared to control cells. Further experiments at the single-cell level and transcriptomic analyses demonstrated that nicotinamide-induced senescence in GB cells is fully reversible. Overall, our findings identify a novel reversible senescent state in GB tumors and highlight the non-canonical role of NAM as a key driver of cancer cell plasticity.

cancer biology↗

bioRxiv2022

Type 1 interferon remodels normal and neoplastic hematopoiesis in human

Inflammation perturbs evolutionary dynamics of hematopoietic stem cell (HSC) clones in clonal hematopoiesis and myeloid neoplasms. We studied HSCs, progenitors and immune cells from patients with myeloproliferative neoplasm (MPN) at baseline and following interferon- (IFN) treatment, the only MPN therapy to deplete clonal stem cells. We focused on essential thrombocythemia, an informative model of early-phase neoplastic hematopoiesis. We integrated somatic genotyping, transcriptomes, immunophenotyping, and chromatin accessibility across single cells. IFN simultaneously activated HSCs into two polarized states, a lymphoid progenitor expansion associated with an anti-inflammatory state and an IFN-specific inflammatory granulocytic progenitor (IGP) state derived directly from HSCs. The augmented lymphoid differentiation balanced the typical MPN-induced myeloid bias, associated with normalized blood counts. Clonal fitness upon IFN exposure was due to resistance of clonal stem cells to differentiate into IGPs. These results support a paradigm wherein inflammation perturbs clonal dynamics by HSC induction into the precipitous IGP differentiation program. One-Sentence SummaryInflammation accelerates clonal evolution by driving stem cell differentiation into an alternate interferon--induced progenitor state.

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↗