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.
2025-04-30 | GSE282756 | 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.
2024-09-17 | GSE266232 | GEO
Project description:Clonal memory, a cellular property inherited across at least two divisions, has emerged as a key driver of cell heterogeneity. To uncover its roles in human haematopoiesis, we developed high-resolution ex vivo tools to track both division and fate commitment of individual primary human haematopoietic stem and progenitor cells (HSPCs). We show that human HSPCs display a clonal memory of division, as cells descending from the same ancestor cell divide synchronously over multiple generations. In parallel, HSPCs inherit a clonal memory of fate commitment, independently of lineage identity. Both forms of clonal memory persist over at least two divisions, across different HSPC commitment stages and cell culture conditions. In contrast, malignant haematopoiesis exhibits lower synchronicity, revealing a disruption of clonal memory in leukemic cells. Epigenetic remodelling using a bromodomain inhibitor partially restore the clonal memory in division in leukemic HSPCs, highlighting the plasticity of this trait and its potential for therapeutic modulation. Our findings position clonal memory as a key regulator of human haematopoietic stem cell behaviour. Demonstrating that clonal memory can be modulated opens new avenues for tuning cell heterogeneity in healthy and pathological tissues.
2026-05-01 | GSE300913 | 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.
2026-03-04 | GSE299711 | 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