Visualizing programmed lineage trajectories at cancer initiation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA639282 | ENA |
REPOSITORIES: ENA
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Project description:The sequential accumulation of survival advantage traits – the cancer evolution hypothesis – implies that early detection and treatment of precancers can prevent cancer mortality. In practice, detection and treatment of breast precancer ductal carcinoma in situ (DCIS) has had minimal impact on reducing breast cancer mortality. The evolution of precancer is not inevitable, suggesting that inciting neoplastic events lead to different trajectories of progression. Here we visualize distinct tumor driver gene programs of lineage specification occurring at cancer initiation. Crainbow fluorescent barcoding of wild-type HER2, d16-HER2, and p95-HER2 enables whole-gland lineage tracing and single-cell reconstruction of the origin of HER2+ breast cancer. Molecular pathology and Crainbow lineage tracing provide genotype:phenotype modules and gene signatures predictive of cancer progression. WT-HER2 neoplasms were rare and proliferative d16-HER2 neoplasms eventually progressed to metastasis, and p95-HER2 induced rapidly invasive and metastatic carcinomas. p95-HER2 carcinomas originate without detectable in situ stages – termed here a minimally detectable “nascent lethal carcinoma”. This nascent lethal program biases the commitment of tumor stem cells toward a metaplastic epithelial-mesenchymal transition-like (EMT) lineage promoting microenvironmental remodeling. Overall, these data suggest that lethality programs begin at initiation, indicating that detection must be improved to identify the nascent lethal lesion.
2021-05-31 | GSE152422 | GEO
Project description:Biologists rely on morphology, function, and specific markers to define the differentiation status of cells. Transcript profiling has expanded the repertoire of these markers by providing the snapshot of cellular status that reflects the activity of all genes. However, such data have been used only to assess relative similarities and differences of these cells. Here we show that principal component analysis (PCA) of global gene expression profiles map cells in multidimensional transcript profile space and the positions of differentiating cells progress in a stepwise manner along trajectories starting from undifferentiated embryonic stem (ES) cells located in the apex. We present three cell lineage trajectories, which represent the differentiation of ES cells into the first three lineages in mammalian development: primitive endoderm, trophoblast, and primitive ectoderm/neural ectoderm. The positions of the cells along these trajectories seem to reflect the developmental potency of cells and can be used as a scale for the potential of cells. Indeed, we show that embryonic germ (EG) cells and induced pluripotent (iPS) cells are mapped near the origin of the trajectories, whereas mouse embryo fibroblast (MEF) and fibroblast cell lines are mapped near the far end of the trajectories. We propose that this method can be used as the non-operational semi-quantitative definition of cell differentiation status and developmental potency. Furthermore, the global expression profiles of cell lineages provide a framework for the future study of in vitro and in vivo cell differentiation. Keywords: cell type comparison design,reference design,replicate design,time series design Most of the cells and RNA samples used in this study were described in detail previously (See paper's citation associated with this dataset). To maximize the uniformity of the microarray data, all the samples, including ones analyzed by DNA microarray previously, were hybridized to the same platform (the NIA Mouse 44K Microarray manufactured by Agilent Technologies: AMADID #015087). The intensity of each gene feature per array was extracted from scanned microarray images using Feature Extraction Software V9.5.
2008-12-27 | E-GEOD-11523 | biostudies-arrayexpress
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Project description:The coordinated spatial and temporal regulation of gene expression in the murine hindlimb determines the identity of mesenchymal progenitors and the development of diversity of musculoskeletal tissues they form. Hindlimb development has historically been studied with lineage tracing of individual genes selected a priori, or at the bulk tissue level, which does not allow for the determination of single cell transcriptional programs yielding mature cell types and tissues. To identify the cellular trajectories of lineage specification during limb bud development, we used single cell mRNA sequencing (scRNA-seq) to profile the developing murine hindlimb.
2020-08-24 | GSE156700 | GEO
Project description:Single cell RNA-sequencing reveals cellular heterogeneity and trajectories of lineage specification
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Project description:Biologists rely on morphology, function, and specific markers to define the differentiation status of cells. Transcript profiling has expanded the repertoire of these markers by providing the snapshot of cellular status that reflects the activity of all genes. However, such data have been used only to assess relative similarities and differences of these cells. Here we show that principal component analysis (PCA) of global gene expression profiles map cells in multidimensional transcript profile space and the positions of differentiating cells progress in a stepwise manner along trajectories starting from undifferentiated embryonic stem (ES) cells located in the apex. We present three cell lineage trajectories, which represent the differentiation of ES cells into the first three lineages in mammalian development: primitive endoderm, trophoblast, and primitive ectoderm/neural ectoderm. The positions of the cells along these trajectories seem to reflect the developmental potency of cells and can be used as a scale for the potential of cells. Indeed, we show that embryonic germ (EG) cells and induced pluripotent (iPS) cells are mapped near the origin of the trajectories, whereas mouse embryo fibroblast (MEF) and fibroblast cell lines are mapped near the far end of the trajectories. We propose that this method can be used as the non-operational semi-quantitative definition of cell differentiation status and developmental potency. Furthermore, the global expression profiles of cell lineages provide a framework for the future study of in vitro and in vivo cell differentiation. Keywords: cell type comparison design,reference design,replicate design,time series design
2008-12-28 | GSE11523 | GEO
Project description:The coordinated spatial and temporal regulation of gene expression in the murine hindlimb determines the identity of mesenchymal progenitors and the development of diversity of musculoskeletal tissues they form. Hindlimb development has historically been studied with lineage tracing of individual genes selected a priori, or at the bulk tissue level, which does not allow for the determination of single cell transcriptional programs yielding mature cell types and tissues. To identify the cellular trajectories of lineage specification during limb bud development, we used single cell mRNA sequencing (scRNA-seq) to profile the developing murine hindlimb between embryonic days (E)11.5-E18.5. We found cell type heterogeneity at all time points, and the expected cell types that form the mouse hindlimb. In addition, we used RNA fluorescence in situ hybridization (FISH) to examine the spatial locations of cell types and cell trajectories to understand the ancestral continuum of cell maturation. This data provides a resource for the transcriptional program of hindlimb development that will support future studies of musculoskeletal development and generate hypotheses for tissue regeneration.
2019-12-21 | GSE142425 | GEO
Project description:The blueprint of lineage segregation of early mouse embryo is established during gastrulation in which progenitors of various cell fates are regionalized and patterned in specific embryo locations. Despite the central importance of this period of mammalian development, we currently lack a comprehensive understanding of the underlying developmental trajectories and molecular processes, principally because research efforts either employed in vitro systems, focused on small numbers of genes, or limited the number of developmental stages or cell types that were studied. Here, we study the regulatory landscape of gastrulation by combining single-cell RNA-seq (A total of ~35,000 single cells isolated at E6.5, E6.75, E7.0, E7.25, E7.5) and geographical position sequencing (Geo-seq) technique, and we report a de novo identification of spatial signatures and a method to enable retrospective locating of single cells to their origins. Our work provides insights into the exit from pluripotency and priming for differentiation, and the emergence of regulatory networks associated with cell fate decisions. Finally, we reconstruct the spatio-temporal roadmap of gastrula mouse embryo in single-cell resolution. This result uncovers the cell migration trajectories and molecular processes associated with lineage segregation.
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