Clonal lineage tracing of innate immune cells in human cancer
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ABSTRACT:
PROVIDER: PRJNA1288771 | ENA |
REPOSITORIES: ENA
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Project description:Innate immune cells constitute the majority of the tumor microenvironment (TME), where they mediate both natural anti-tumor immunity and immunotherapy responses. While single-cell T- and B-cell receptor sequencing has provided fundamental insights into the clonal dynamics of human adaptive immunity, the lack of appropriate tools has precluded similar analysis of innate immune cells. Here, we developed a method leveraging somatic mitochondrial DNA (mtDNA) mutations to reconstruct clonal lineage relationships between single cells across native human tissues. We jointly sequenced single-cell transposase-accessible chromatin and mtDNA to profile 124,958 cells from matched tumor, non-involved lung tissue (NILT) with peripheral blood of early-stage non-small cell lung cancer (NSCLC) patients, as well as 93,757 cells from matched tumor and peripheral blood of ovarian cancer patients. Our single-cell concomitant profiling of lineage and cell states of thousands of immune cells resolved clonality across cell types, tissue sites, and malignancies. By resolving clonal populations across innate immune subtypes, we demonstrated that TME-resident myeloid subsets, including macrophages and type 3 dendritic cells (DC3), are clonally linked to both circulating and tissue-infiltrating monocytes. Further, we identified distinct DC-biased and macrophage-biased myeloid clones, enriched in the tumor and NILT, respectively, and found that their circulating monocyte precursors exhibit distinct epigenetic profiles, suggesting that myeloid differentiation fate may be predetermined before TME infiltration. These results delineate the clonal pathways of intratumoral myeloid cell recruitment and differentiation in human cancer and suggest that remodeling of the tumor myeloid compartment may be peripherally programmed.
2025-09-08 | GSE302113 | GEO
Project description:Developmental origins of dendritic cells (DCs) including conventional DCs (cDCs, comprising cDC1 and cDC2 subsets) and plasmacytoid DCs (pDCs) remain unclear. We studied DC development in unmanipulated adult mice using inducible lineage tracing combined with clonal DNA "barcoding" and single-cell transcriptome and phenotype analysis (CITE-Seq). Inducible tracing of Cx3cr1+ hematopoietic progenitors in the bone marrow showed that they simultaneously produce all DC subsets including pDCs, cDC1s and cDC2s. Clonal tracing of hematopoietic stem cells (HSCs) and of Cx3cr1+ progenitors revealed clone sharing between cDC1s and pDCs, but not between the two cDC subsets or between pDCs and B cells. Accordingly, CITE-Seq analyses of differentiating HSCs and Cx3cr1+ progenitors identified progressive stages of pDC development including Cx3cr1+ Ly-6D+ propDCs that were distinct from lymphoid progenitors. These results reveal the shared origin of pDCs and cDCs, and suggest a revised scheme of DC development whereby pDCs share clonal relationship with cDC1s
2022-02-16 | GSE193733 | GEO
Project description:In vivo clonal analysis utilizing recombinase-activated fluorescence cell labeling has become an essential method for visualizing stem cell activities and cell lineage formation. Recently, the simultaneous acquisition of cell lineage information and single-cell transcriptome data has further advanced our understanding of clonal cell evolution during development, tissue homeostasis, and disease progression. Here we present a novel inducible cell lineage tracing system, called TiTracer, which simultaneously activates fluorescence cell labeling and cellular barcode generation by transiently expressing template independent terminal transferase (TdT) and I-SceI homing endonuclease. We applied this system in HEK293T cells and primary mouse keratinocytes and performed single-cell RNA-seq for barcode recovery and clonal reconstruction.
2025-03-15 | GSE227531 | GEO
Project description:Clonal lineage tracing reveals shared origin of conventional and plasmacytoid dendritic cells
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Project description:Cell plasticity is a core biological process underlying a myriad of molecular and cellular events taking place throughout organismal development and evolution. It has been postulated that cellular systems thrive to balance the organization of meta-stable states underlying this phenomenon, thus maintaining a degree of populational homeostasis compatible with an ever-changing environment and, thus, life. Notably, albeit circumstantial evidence has been gathered in favour of the latter conceptual framework, a direct observation of meta-state dynamics and the biological consequences of such a process in generating non-genetic clonal diversity and divergent phenotypic output remains largely unexplored. To fill this void, we developed a lineage-tracing technology termed Barcode-decay Lineage Tracing-Seq. BdLT-Seq is based on episome-encoded molecular identifiers that, supported by the dynamic decay of the tracing information upon cell division, ascribe directionality to a cell lineage tree in a time-resolved manner whilst directly coupling non-genetic molecular features to phenotypes in comparable genomic landscapes. Herein we show that cell transcriptome states are both inherited and dynamically reshaped following constrained rules encoded within the cell lineage, leading to intra-clonal non-genetic diversity in basal growth conditions and while adjusting populational phenotypic output upon oncogene activation and throughout the process of reversible resistance to therapeutic cues.
2023-02-11 | GSE223490 | GEO
Project description:Cell plasticity is a core biological process underlying a myriad of molecular and cellular events taking place throughout organismal development and evolution. It has been postulated that cellular systems thrive to balance the organization of meta-stable states underlying this phenomenon, thus maintaining a degree of populational homeostasis compatible with an ever-changing environment and, thus, life. Notably, albeit circumstantial evidence has been gathered in favour of the latter conceptual framework, a direct observation of meta-state dynamics and the biological consequences of such a process in generating non-genetic clonal diversity and divergent phenotypic output remains largely unexplored. To fill this void, we developed a lineage-tracing technology termed Barcode-decay Lineage Tracing-Seq. BdLT-Seq is based on episome-encoded molecular identifiers that, supported by the dynamic decay of the tracing information upon cell division, ascribe directionality to a cell lineage tree in a time-resolved manner whilst directly coupling non-genetic molecular features to phenotypes in comparable genomic landscapes. Herein we show that cell transcriptome states are both inherited and dynamically reshaped following constrained rules encoded within the cell lineage, leading to intra-clonal non-genetic diversity in basal growth conditions and while adjusting populational phenotypic output upon oncogene activation and throughout the process of reversible resistance to therapeutic cues.
2023-02-11 | GSE223491 | GEO
Project description:Cell plasticity is a core biological process underlying a myriad of molecular and cellular events taking place throughout organismal development and evolution. It has been postulated that cellular systems thrive to balance the organization of meta-stable states underlying this phenomenon, thus maintaining a degree of populational homeostasis compatible with an ever-changing environment and, thus, life. Notably, albeit circumstantial evidence has been gathered in favour of the latter conceptual framework, a direct observation of meta-state dynamics and the biological consequences of such a process in generating non-genetic clonal diversity and divergent phenotypic output remains largely unexplored. To fill this void, we developed a lineage-tracing technology termed Barcode-decay Lineage Tracing-Seq. BdLT-Seq is based on episome-encoded molecular identifiers that, supported by the dynamic decay of the tracing information upon cell division, ascribe directionality to a cell lineage tree in a time-resolved manner whilst directly coupling non-genetic molecular features to phenotypes in comparable genomic landscapes. Herein we show that cell transcriptome states are both inherited and dynamically reshaped following constrained rules encoded within the cell lineage, leading to intra-clonal non-genetic diversity in basal growth conditions and while adjusting populational phenotypic output upon oncogene activation and throughout the process of reversible resistance to therapeutic cues.
2023-02-11 | GSE223495 | GEO
Project description:Cell plasticity is a core biological process underlying a myriad of molecular and cellular events taking place throughout organismal development and evolution. It has been postulated that cellular systems thrive to balance the organization of meta-stable states underlying this phenomenon, thus maintaining a degree of populational homeostasis compatible with an ever-changing environment and, thus, life. Notably, albeit circumstantial evidence has been gathered in favour of the latter conceptual framework, a direct observation of meta-state dynamics and the biological consequences of such a process in generating non-genetic clonal diversity and divergent phenotypic output remains largely unexplored. To fill this void, we developed a lineage-tracing technology termed Barcode-decay Lineage Tracing-Seq. BdLT-Seq is based on episome-encoded molecular identifiers that, supported by the dynamic decay of the tracing information upon cell division, ascribe directionality to a cell lineage tree in a time-resolved manner whilst directly coupling non-genetic molecular features to phenotypes in comparable genomic landscapes. Herein we show that cell transcriptome states are both inherited and dynamically reshaped following constrained rules encoded within the cell lineage, leading to intra-clonal non-genetic diversity in basal growth conditions and while adjusting populational phenotypic output upon oncogene activation and throughout the process of reversible resistance to therapeutic cues.
2023-02-11 | GSE223494 | GEO
Project description:Cell plasticity is a core biological process underlying a myriad of molecular and cellular events taking place throughout organismal development and evolution. It has been postulated that cellular systems thrive to balance the organization of meta-stable states underlying this phenomenon, thus maintaining a degree of populational homeostasis compatible with an ever-changing environment and, thus, life. Notably, albeit circumstantial evidence has been gathered in favour of the latter conceptual framework, a direct observation of meta-state dynamics and the biological consequences of such a process in generating non-genetic clonal diversity and divergent phenotypic output remains largely unexplored. To fill this void, we developed a lineage-tracing technology termed Barcode-decay Lineage Tracing-Seq. BdLT-Seq is based on episome-encoded molecular identifiers that, supported by the dynamic decay of the tracing information upon cell division, ascribe directionality to a cell lineage tree in a time-resolved manner whilst directly coupling non-genetic molecular features to phenotypes in comparable genomic landscapes. Herein we show that cell transcriptome states are both inherited and dynamically reshaped following constrained rules encoded within the cell lineage, leading to intra-clonal non-genetic diversity in basal growth conditions and while adjusting populational phenotypic output upon oncogene activation and throughout the process of reversible resistance to therapeutic cues.
2023-02-11 | GSE223492 | GEO
Project description:Cell plasticity is a core biological process underlying a myriad of molecular and cellular events taking place throughout organismal development and evolution. It has been postulated that cellular systems thrive to balance the organization of meta-stable states underlying this phenomenon, thus maintaining a degree of populational homeostasis compatible with an ever-changing environment and, thus, life. Notably, albeit circumstantial evidence has been gathered in favour of the latter conceptual framework, a direct observation of meta-state dynamics and the biological consequences of such a process in generating non-genetic clonal diversity and divergent phenotypic output remains largely unexplored. To fill this void, we developed a lineage-tracing technology termed Barcode-decay Lineage Tracing-Seq. BdLT-Seq is based on episome-encoded molecular identifiers that, supported by the dynamic decay of the tracing information upon cell division, ascribe directionality to a cell lineage tree in a time-resolved manner whilst directly coupling non-genetic molecular features to phenotypes in comparable genomic landscapes. Herein we show that cell transcriptome states are both inherited and dynamically reshaped following constrained rules encoded within the cell lineage, leading to intra-clonal non-genetic diversity in basal growth conditions and while adjusting populational phenotypic output upon oncogene activation and throughout the process of reversible resistance to therapeutic cues.
2023-02-11 | GSE223484 | GEO