Biology subjects

Lungu, I.

Publications and source records attributed to Lungu, I..

3 recordsLinked to original sources

bioRxiv2026

Extra-lineage tissue programs define the transcription states of human pancreatic cancer

Cancers acquire alternate transcriptional states as they evolve, but the origins, timing and determinants of this plasticity are poorly understood in many tumours. We investigated the transcriptional states of pancreatic cancer by integrating [~]1000 tumour-enriched genomes and transcriptomes from 464 patients combined with scRNA-seq, multiome profiling, and spatial proteomics. Four epithelial states covering the spectrum of lineage plasticity were identified (Classical-1, Classical-2, Basal-1, Basal-2). Comparing these states to normal and pan-cancer human single cell atlases showed each state reflects distinct tissue programs found in other malignancies. Single cell analysis uncovered that the main transcription state of this disease (Classical-1) emerges before KRAS mutations. Spatial proteomics from patients and cancer-free donors showed that the Classical-1 program emerges during acinar-to-ductal metaplasia, and also unexpectedly, in normal ducts without disrupting their morphology. Overall, these findings link the extensive lineage plasticity potential of this organ to the origins of the transcriptional states.

cancer biology↗

bioRxiv2025

Epigenomic landscape of the developing human rhombic lip reveals gene regulatory network and non-coding loci of developmental, evolutionary, and disease relevance

The cerebellar rhombic lip neural progenitor niche of the prenatal hindbrain is an anatomical structure critical for cerebellar glutamatergic neurogenesis. Humans have elaborated the rhombic lip niche to include a rhombic lip subventricular zone (RL-SVZ) not seen in mice or macaques. Although developmental disruptions of this progenitor zone can cause cerebellar growth abnormalities - from malformations to tumors - the gene regulatory networks underpinning this unique progenitor niche are unknown. Here we provide a predicted gene regulatory network for the human cerebellar rhombic lip, inferred from epigenomic maps of the developing human cerebellum. We generated DNA methylomes of neuroanatomically-dissected mid-gestation human rhombic lip ventricular zone and RL-SVZ (N=9 samples; 15-16 post conception weeks) using low-input Enzymatic MethylSeq. We also mapped histone modifications marking active promoters and enhancers in the whole mid-gestation human fetal cerebellum (N=6 samples; 14 and 18 post-conception weeks). Integrating these data, we identified 9,855 differentially-methylated regions (DMR) which converge on binding sites of over three hundred transcription factors, including master regulators of rhombic lip neurogenesis, ATOH1, NEUROD1, and NEUROD2. DMRs hypomethylated in the RL-SVZ are enriched in active enhancers and in human accelerated regions, and are depleted in active promoters. We inferred 81,844 transcription factor-enhancer-gene links, covering 41 transcription factors active in the rhombic lip, and 4,610 target genes that include drivers of cerebellar neurogenesis and pediatric hindbrain cancer. Twenty-five DMRs overlap human accelerated regions located near genes associated with intellectual disability, autism spectrum disorders, and neurological deficits. DMRs are also statistically enriched in copy number aberrations in medulloblastoma, a malignant pediatric hindbrain cancer with subtypes hypothesized to originate in the rhombic lip. Close to one-quarter of the DMRs overlap known copy number aberrations in medulloblastoma, nominating potential enhancer and promoter elements impacted by these genomic aberrations. Collectively, our data provide a rich resource to start decoding the functional impact of non-coding variation on gene regulation in the developing cerebellum and on genomic dysregulation in diseases of cerebellar growth.

developmental biology↗

bioRxiv2018

Meta-analysis of 1,200 transcriptomic profiles identifies a prognostic model for pancreatic ductal adenocarcinoma

BackgroundWith a dismal 8% median 5-year overall survival (OS), pancreatic ductal adenocarcinoma (PDAC) is highly lethal. Only 10-20% of patients are eligible for surgery, and over 50% of these will die within a year of surgery. Identify molecular predictors of early death would enable the selection of PDAC patients at high risk.\n\nMethodsWe developed the Pancreatic Cancer Overall Survival Predictor (PCOSP), a prognostic model built from a unique set of 89 PDAC tumors where gene expression was profiled using both microarray and sequencing platforms. We used a meta-analysis framework based on the binary gene pair method to create gene expression barcodes robust to biases arising from heterogeneous profiling platforms and batch effects. Leveraging the largest compendium of PDAC transcriptomic datasets to date, we show that PCOSP is a robust single-sample predictor of early death ([≤]1 yr) after surgery in a subset of 823 samples with available transcriptomics and survival data.\n\nResultsThe PCOSP model was strongly and significantly prognostic with a meta-estimate of the area under the receiver operating curve (AUROC) of 0.70 (P=1.9e-18) and hazard ratio (HR) of 1.95(1.6-2.3) (P=2.6e-16) for binary and survival predictions, respectively. The prognostic value of PCOSP was independent of clinicopathological parameters and molecular subtypes. Over-representation analysis of the PCOSP 2619 gene-pairs (1070 unique genes) unveiled pathways associated with Hedgehog signalling, epithelial mesenchymal transition (EMT) and extracellular matrix (ECM) signalling.\n\nConclusionPCOSP could improve treatment decision by identifying patients who will not benefit from standard surgery/chemotherapy and may benefit from alternate approaches.\n\nAbbreviations

genomics↗