ABSTRACT: Multi-omics data and stochastic simulations support a cancer heterogeneity framework unifying genetic, epigenetic, and stochastic variabilities [Bulk-WXS-seq] (human)
Project description:Multi-omics data and stochastic simulations support a cancer heterogeneity framework unifying genetic, epigenetic, and stochastic variabilities
Project description:Multi-omics data and stochastic simulations support a cancer heterogeneity framework unifying genetic, epigenetic, and stochastic variabilities [Bulk-RNA-seq]
Project description:Multi-omics data and stochastic simulations support a cancer heterogeneity framework unifying genetic, epigenetic, and stochastic variabilities [scRNA-seq]
Project description:We subject multiple versions and single cell-derived sublines of an archetypal non-small cell lung cancer cell line to experimental scrutiny at the genomic, transcriptomic, and cell population levels. We find evidence of genetic variability among cell line versions and one subline. Additional sublines show no genetic variation but epigenetic differences are detected at the transcriptomic level. Stochastic simulations of subline growth dynamics confirm that one subline likely contains at least two genetic states while all others are isogenic. Overall, our results substantiate a view of intratumoral heterogeneity in which different genetic states give rise to multiple epigenetic “basins of attraction,” across which cells can transition driven by stochastic factors such as gene expression noise and asymmetric cell division. Deconvolving intratumoral heterogeneity into genetic, epigenetic, and stochastic components provides a lens through which to view tumor drug response and acquired treatment resistance that may lead to novel therapeutic strategies in the future.
Project description:We subject multiple versions and single cell-derived sublines of an archetypal non-small cell lung cancer cell line to experimental scrutiny at the genomic, transcriptomic, and cell population levels. We find evidence of genetic variability among cell line versions and one subline. Additional sublines show no genetic variation but epigenetic differences are detected at the transcriptomic level. Stochastic simulations of subline growth dynamics confirm that one subline likely contains at least two genetic states while all others are isogenic. Overall, our results substantiate a view of intratumoral heterogeneity in which different genetic states give rise to multiple epigenetic “basins of attraction,” across which cells can transition driven by stochastic factors such as gene expression noise and asymmetric cell division. Deconvolving intratumoral heterogeneity into genetic, epigenetic, and stochastic components provides a lens through which to view tumor drug response and acquired treatment resistance that may lead to novel therapeutic strategies in the future.
Project description:Although genomic instability, epigenetic abnormality, and gene expression dysregulation are hallmarks of colorectal cancer, these features have not been simultaneously analyzed at single-cell resolution. Using optimized single-cell multi-omics sequencing together with multi-regional sampling of the primary tumor, lymphatic and distant metastases, we provide insights beyond intratumoral heterogeneity. Genome-wide DNA methylation levels were relatively consistent within a single genetic sub-lineage. The genome-wide DNA demethylation patterns of cancer cells were consistent in all 10 sequenced patients. Our work demonstrates the feasibility of reconstructing genetic lineages, and tracing their epigenomic and transcriptomic dynamics with single-cell multi-omics sequencing.
Project description:Using single-cell RNA sequencing, spatial transcriptomic and bulk multi-omics, we elaborated a molecular architecture of 3 PLC types, namely hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular-cholangiocarcinoma (CHC) from a high-resolution perspective.
Project description:We develop an R/Bioconductor package CancerInSilico to simulate bulk and single cell transcriptional data from a known ground truth obtained from mathematical models of cellular systems. This package contains a general R infrastructure for cell-based mathematical model, implemented for an off-lattice, cell-center Monte Carlo mathematical model. We also adapt this model to simulate the impact of growth suppression by targeted therapeutics in cancer and benchmark simulations against bulk in vitro experimental data. Sensitivity to parameters is evaluated and used to predict the relative impact of variation in cellular growth parameters and cell types on tumor heterogeneity in therapeutic response.
Project description:Single cell RNA-sequencing revealed extensive transcriptional cell state diversity in cancer, often observed independently from genetic heterogeneity, raising the central question of how malignant cell states are encoded epigenetically. To address this, we performed multi-omics single-cell profiling – integrating DNA methylation, transcriptome, and genotyping within the same cells – of diffuse gliomas, tumors characterized by defined transcriptional cell state diversity. Direct comparison of the epigenetic profiles of distinct cell states revealed key switches for state transitions recapitulating neurodevelopmental trajectories, and highlighted dysregulated epigenetic mechanisms underlying gliomagenesis. We further developed a quantitative framework to measure cell state heritability and transition dynamics based on high resolution lineage trees directly in human samples. We demonstrated heritability of malignant cell states, with key differences in hierarchal vs. plastic cell state architectures in IDH-mutant glioma vs. IDH-wildtype glioblastoma, respectively. This work provides a framework anchoring transcriptional cancer cell states in their epigenetic encoding, inheritance and transition dynamics.
