Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA362615 | ENA |
REPOSITORIES: ENA
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Project description:To probe the phenotypic heterogeneity found in cell populations, we developed an image-guided genomics technique termed spatiotemporal genomic and cellular analysis (SaGA) that allows for precise selection and amplification of living and rare cells. SaGA was used on collectively invading 3-D cancer cell packs to create purified leader and follower cell lines. The leader cell cultures are phenotypically stable and highly invasive in contrast to follower cultures, which show phenotypic plasticity over time and minimally invade in a sheet-like pattern. Genomic and molecular interrogation reveals an atypical VEGF-based vasculogenesis signaling that facilitates recruitment of follower cells but not for leader cell motility itself, which instead utilizes focal adhesion kinase-fibronectin signaling. While leader cells provide an escape mechanism for followers, follower cells in turn provide leaders with increased growth and survival. These data support a symbiotic model of collective invasion where phenotypically distinct cell types cooperate to promote their escape. A single tumor can harbor distinct genetic and epigenetic cellular sub-populations that drive tumor initiation and progression. This intratumor heterogeneity is proposed to be one of the major confounding factors of treatment causing relapse and poor clinical outcome1. Genomic instability and epigenetic modifications generate intratumor heterogeneity creating distinct genetic and epigenetic sub-populations or clones. A branched tumor evolutionary architecture can emerge containing the plasticity to progress under harsh environmental conditions and thwart therapeutic attempts to eradicate the tumor. It can be argued that until we discover how intratumor heterogeneity can be circumvented, precision oncology initiatives may fall short of expectations. Single cell sequencing methodologies have improved the genomic, transcriptomic, and epigenomic resolution of clonal tumor populations; however, the phenotypic implications of these alterations remain unclear. This is partly due to experimental challenges and is compounded by phenotypic plasticity that allows cancer cells to adapt to local changes in the microenvironment, without changes to the genome itself (e.g., epithelial to mesenchymal transition). Despite repeated observations that a small number of rare cancer cells or clones, hidden within a larger tumor population can drive tumor growth and spread, studies linking single cell or clonal phenotypes with genomic data have been limited. To probe the biology of a rare and phenotypically heterogeneous cell populations, single cells or subclones need to be isolated based upon user-defined criteria, instead of a random isolation approach; therefore, we developed a technique to image live cells within a biologically relevant 3-D environment, select a cell or cellular group based upon user-defined criteria, extract the cell(s), and subject the cell(s) to genomic and molecular analyses. In this way, we can purify, amplify, and systematically dissect the biologies of rare cells. This new technique, termed spatiotemporal genomic and cellular analysis (SaGA), was used to dissect the phenotypic heterogeneity of collective cancer cell invasion in a 3-D lung cancer model. These data incorporate the first SaGA-derived leader and follower cell lines to reveal that leader cells utilize atypical vasculogenesis signaling machinery by secreting VEGF to attract follower cells in invasive cell chains. In contrast, follower cells support leader cell growth by increasing their mitotic efficiency. This relationship argues for a cellular symbiosis within the collective invasion pack. Furthermore, these data provide proof of concept that SaGA is a powerful technology for dissecting phenotypic heterogeneity within cancer cell populations.
2017-02-10 | GSE93865 | GEO
Project description:The vascular endothelium contains morphologically similar cells throughout, but individual cells along the length of a single vascular tree or in different regional circulations function quite dissimilarly. When observations made in large arteries are extrapolated to explain the function of endothelial cells (EC) in the resistance vasculature/microcirculation, only a fraction of these observations are consistent between artery sizes. To what extent endothelial (EC) and vascular smooth muscle (VSMC) cells from different arteriolar segments of the same tissue differ phenotypically at the single-cell level remains unknown. Therefore, single-cell RNA-seq (10x Genomics) was performed using a 10X Genomics Chromium system.
2023-03-09 | GSE202244 | GEO
Project description:Breast tumors often exhibit intratumoral heterogeneity. We hypothesized that phenotypically distinct clonal subpopulations in heterogeneous tumors may affect overall tumor morphology and cancer cell invasion. In order to study heterogeneous tumors, we isolated individual cells from a parental 4T1 murine mammary carcinoma cell line and generated four clonal subpopulations (E1, E2, A, and M). To characterize these subpopulations, we examined gene expression by performing bulk RNA-sequencing.
2024-01-31 | GSE252177 | GEO
Project description:To confirm the role of the collective dissemination in the mechanisms of tumoral invasion of colorectal cancers
| 2279691 | ecrin-mdr-crc
Project description:Tumor heterogeneity drives disease progression, treatment resistance, and patient relapse, yet remains largely under-explored in invasion and metastasis. Here, we investigated heterogeneity within collective cancer invasion by integrating DNA methylation and gene expression analysis in rare purified lung cancer leader and follower cells. Our results showed global DNA methylation rewiring in leader cells and revealed the filopodial motor MYO10 as a critical gene at the intersection of epigenetic heterogeneity and 3D collective invasion. We further identified JAG1 signaling as a novel upstream activator of MYO10 expression in leader cells. Using live cell imaging, we discovered that MYO10 drives filopodial persistence necessary for micropatterning extracellular fibronectin into linear tracks at the edge of 3D collective invasion exclusively in leaders. Our data fit a model where epigenetic heterogeneity and JAG1/Notch signaling jointly drive collective cancer invasion through MYO10 upregulation in epigenetically permissive leader cells, which induces filopodia dynamics necessary for linearized fibronectin micropatterning.
2020-07-31 | GSE147153 | GEO
Project description:Triple negative breast tumors contain heterogeneous cancer cells expressing distinct KRAS-dependent collective and disseminative invasion programs
| PRJNA888356 | ENA
Project description:Characterizing phenotypically distinct T cell populations
| PRJNA648405 | ENA
Project description:Collective cell migration is one of the principal modes for cancer cell movements. However, the triggering event for collective migration and its clinical significance is unclear. Here, we found that Snail, a major inducer of epithelial-mesenchymal transition (EMT), is critical for orchestrating collective migration in squamous cell carcinoma (SCC). To invstigate how Snail contribute to collective migration and invasion, we used microarrays to identify the global gene alterations regulated by Snail in SCC cells.
2018-08-25 | GSE87841 | GEO
Project description:Inter-patient and intra-tumoral heterogeneity complicate the identification of predictive biomarkers and effective treatments for basal triple negative breast cancer (b-TNBC). Invasion is the initiating event in metastasis and can occur by both collective and single-cell mechanisms. We cultured primary organoids from a b-TNBC genetically engineered mouse model in 3D collagen gels to characterize their invasive behavior. We observed that organoids from the same tumor presented different phenotypes that we classified as non-invasive, collective and disseminative. To identify molecular regulators driving these invasive phenotypes, we developed a workflow to isolate individual organoids from the collagen gels based on invasive morphology and perform RNA sequencing. We next tested the requirement of differentially regulated genes for invasion using shRNA knock-down. Strikingly, KRAS was required for both collective and disseminative phenotypes. We then performed a drug screen targeting signaling nodes upstream and downstream of KRAS. We found that inhibition of EGFR, MAPK/ERK, or PI3K/AKT signaling reduced invasion. Of these, ERK inhibition was striking for its ability to potently inhibit collective invasion and dissemination. We conclude that different cancer cells in the same b-TNBC tumor can express different metastatic molecular programs and identified KRAS and ERK as essential regulators of collective and single cell dissemination.
2023-01-03 | GSE215069 | GEO
Project description:Colorectal cancer (CRC) cells infiltrating surrounding tissue commonly undergo partial epithelial-mesenchymal transitions (pEMT) and employ a collective mode of invasion. How these phenotypic traits are regulated and possibly interconnected remains underexplored. Here, we used intestinal organoids with CRC driver mutations as model system to investigate the mechanistic basis of TGF‑β1-induced pEMT and collective invasion. By scRNA-seq we identified multiple cell subpopulations representing a broad pEMT spectrum, where the most advanced pEMT state correlated with the transcriptional profiles of leader cells in collective invasion and a poor prognosis mesenchymal subtype in human CRC. Bioinformatic analyses pinpointed Sox11 as a transcription factor whose expression peaked in the potential leader/pEMThigh cells. Immunofluorescence staining confirmed Sox11 expression in cells at the invasive front of TGF‑β1-treated organoids. Loss-of-function and overexpression experiments showed that Sox11 is necessary, albeit not sufficient, for TGF-β1-induced pEMT and collective invasion. In human CRC samples, elevated Sox11 expression was associated with advanced tumor stages and worse prognosis. Unexpectedly, aside from orchestrating the organoid response to TGF-β1, Sox11 controlled expression of genes related to normal gut function and tumor suppression. Apparently, Sox11 is embedded in several, distinct gene regulatory circuits, contributing to intestinal tissue homeostasis, tumor suppression, and TGF-β-mediated cancer cell invasion.
2025-05-20 | GSE278490 | GEO