Ontology highlight
ABSTRACT:
PROVIDER: PRJEB13491 | ENA |
REPOSITORIES: ENA
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Project description:Tumors with the same driver mutations can display a striking variation in their progression and treatment response, but the origins of this variation are still unclear. In this study, we use state-fate analysis to unveil that heritable stem cell states can influence how individual cells respond to the acquisition of the same cancer mutation. We develop a new methodological pipeline, single-cell Tracking of Recombinase Activation And Clonal Kinetics, and apply it to hematopoietic stem cells carrying Cre/Flp-conditional leukemia alleles. Tracking the gene expression changes and expansion kinetics of a common set of stem cell clones, with and without the same myeloid leukemia mutations, we unveil a striking heterogeneity in the malignant fates of diverse stem cells. First, we define that heritable clonal states persist in expansion cultures and cause the selection of a small group of clones with a specific fitness signature. Then, using mouse models of the most frequent initiating mutations, we define that these pre-existent stem cell states influence the mutation-induced changes in expansion, fate, and malignant gene expression programs. Initiating driver mutations increase the survival probability of clones with low fitness through enhancing their stemness programs. Surprisingly, the fate of high-fitness stem-cell clones is sometimes reversed, producing more mature leukemias, yet still carrying markers of their cell of origin. We further validate these HSC-of-origin signatures in bulk and single-cell RNAseq datasets from cancer patients. Our findings suggest that aggressive premalignant clonal expansions arise from low-fitness stem cells more frequently than previously expected.
2024-09-17 | GSE266232 | GEO
Project description:Tumors with the same driver mutations can display a striking variation in their progression and treatment response, but the origins of this variation are still unclear. In this study, we use state-fate analysis to unveil that heritable stem cell states can influence how individual cells respond to the acquisition of the same cancer mutation. We develop a new methodological pipeline, single-cell Tracking of Recombinase Activation And Clonal Kinetics, and apply it to hematopoietic stem cells carrying Cre/Flp-conditional leukemia alleles. Tracking the gene expression changes and expansion kinetics of a common set of stem cell clones, with and without the same myeloid leukemia mutations, we unveil a striking heterogeneity in the malignant fates of diverse stem cells. First, we define that heritable clonal states persist in expansion cultures and cause the selection of a small group of clones with a specific fitness signature. Then, using mouse models of the most frequent initiating mutations, we define that these pre-existent stem cell states influence the mutation-induced changes in expansion, fate, and malignant gene expression programs. Initiating driver mutations increase the survival probability of clones with low fitness through enhancing their stemness programs. Surprisingly, the fate of high-fitness stem-cell clones is sometimes reversed, producing more mature leukemias, yet still carrying markers of their cell of origin. We further validate these HSC-of-origin signatures in bulk and single-cell RNAseq datasets from cancer patients. Our findings suggest that aggressive premalignant clonal expansions arise from low-fitness stem cells more frequently than previously expected.
2025-04-30 | GSE282755 | GEO
Project description:Tumors with the same driver mutations can display a striking variation in their progression and treatment response, but the origins of this variation are still unclear. In this study, we use state-fate analysis to unveil that heritable stem cell states can influence how individual cells respond to the acquisition of the same cancer mutation. We develop a new methodological pipeline, single-cell Tracking of Recombinase Activation And Clonal Kinetics, and apply it to hematopoietic stem cells carrying Cre/Flp-conditional leukemia alleles. Tracking the gene expression changes and expansion kinetics of a common set of stem cell clones, with and without the same myeloid leukemia mutations, we unveil a striking heterogeneity in the malignant fates of diverse stem cells. First, we define that heritable clonal states persist in expansion cultures and cause the selection of a small group of clones with a specific fitness signature. Then, using mouse models of the most frequent initiating mutations, we define that these pre-existent stem cell states influence the mutation-induced changes in expansion, fate, and malignant gene expression programs. Initiating driver mutations increase the survival probability of clones with low fitness through enhancing their stemness programs. Surprisingly, the fate of high-fitness stem-cell clones is sometimes reversed, producing more mature leukemias, yet still carrying markers of their cell of origin. We further validate these HSC-of-origin signatures in bulk and single-cell RNAseq datasets from cancer patients. Our findings suggest that aggressive premalignant clonal expansions arise from low-fitness stem cells more frequently than previously expected.
2025-04-30 | GSE282756 | GEO
Project description:Most advanced cancers initially respond to targeted therapies but eventually relapse1. Rather than acquiring new mutations, resistance is driven by drug-tolerant persister cells (DTP) that enter a reversible drug-refractory state and sustain minimal residual disease2. Here, we developed MeRLin, a high-resolution barcoding platform combining single-cell RNA sequencing, RNA fluorescence in situ hybridization, and computational analyses to track clonal and transcriptional dynamics of melanoma cells during targeted therapy. Clonal tracking reveals that dominant resistant clones arise from minor pre-treatment subpopulations. The pre-treatment melanoma populations diversify into phenotypically distinct DTP subpopulations, marked by stress-like, lipid metabolism, PI3K signaling, and extracellular matrix remodeling programs associated with adaptive resistance. Spatial transcriptomics revealed the co-localization of lipid metabolism and PI3K signaling programs near the tumor boundaries, and a complex network of autocrine and paracrine interactions among DTP subpopulations. Using barcoded RNA fluorescence in situ hybridization, we identified a dominant persister subpopulation in resistant tumors marked by SLC2A1 expression. Thus, MeRLin provides a robust framework to dissect melanoma heterogeneity and uncover vulnerabilities in persister populations to improve long-term treatment efficacy.
2026-02-18 | GSE299589 | GEO
Project description:Understanding clonal evolution and cancer development requires experimental approaches for characterizing the consequences of somatic mutations on gene regulation. However, no methods currently exist that efficiently link chromatin accessibility with genotype in single cells. To address this, we developed Genotyping with the Assay for Transposase-Accessible Chromatin (GTAC), enabling accurate mutation detection at multiple amplified loci, coupled with robust chromatin accessibility readout. We applied GTAC to primary acute myeloid leukemia, obtaining high-quality chromatin accessibility profiles and clonal identities for multiple mutations in 88% of cells. We traced chromatin variation throughout clonal evolution, showing the restriction of different clones to distinct differentiation stages. Furthermore, we identified switches in transcription factors motif accessibility associated with a specific combination of driver mutations, which biased transformed progenitors towards a leukemia stem cell-like chromatin state. GTAC is a powerful tool to study clonal heterogeneity across a wide spectrum of pre-malignant and neoplastic conditions.
2023-05-04 | GSE214812 | GEO
Project description:Intratumoral heterogeneity is well-recognized but its impact on tumor progression is unclear. Here, we derived unbiased clonal populations from OCI-C5x, a patient-derived ovarian clear cell carcinoma cell line, and assessed their tumorigenicity and tracked their fate during tumor progression. Results provide insight into intratumoral heterogeneity of clear cell carcinoma transcriptomes.
2020-09-11 | GSE123426 | GEO
Project description:Cancer evolution is a multifaceted process involving the acquisition of somatic mutations and progressive epigenetic dysregulation of cellular fate. Both cell-intrinsic mechanisms and environmental interactions provide selective pressures capable of promoting clonal evolution and expansion, with single-cell and bulk DNA sequencing offering increased resolution into this process. Advances in genome editing, single-cell biology and expressed lentiviral barcoding have enabled new insights into how transcriptional/epigenetic states change with clonal evolution. Despite the extensive catalog of genomic alterations revealed by resequencing studies, there remain limited means to functionally model and perturb this evolutionary process in experimental systems. Here we integrated multi-recombinase (Cre, Flp, and Dre) tools for modeling reversible, sequential mutagenesis from premalignant clonal hematopoiesis to acute myeloid leukemia. We demonstrate that somatic acquisition of Flt3 activating mutations elicits distinct phases of acute and chronic activation resulting in differential cooperativity with Npm1 and Dnmt3a disease alleles. We next developed a generalizable allelic framework allowing for the reversible expression of oncogenic mutations at their endogenous loci. We found that reversal of mutant Flt3 resulted in rapid leukemic regression with distinct alterations in cellular compartments depending upon co-occurring mutations. These studies provide a path to model sequential mutagenesis and deterministically investigate mechanisms of transformation and oncogenic dependency in the context of clonal evolution.
2022-05-25 | GSE203454 | GEO