Cancer cell states recur across tumor types and form specific interactions with the tumor microenvironment
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE203612 | GEO | 2022/08/05
REPOSITORIES: GEO
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Project description:The complexity of the tumor microenvironment poses significant challenges in cancer therapy. Here, to comprehensively investigate the tumor-normal ecosystems, we perform an integrative analysis of 4.9 million single-cell transcriptomes from 1,070 tumor and 493 normal samples in combination with pan-cancer 137 spatial transcriptomics, 8,887 TCGA, and 1,261 checkpoint inhibitor-treated bulk tumors. We define a myriad of cell states constituting the tumor-normal ecosystems and also identify hallmark gene signatures across different cell types and organs. Our atlas characterizes distinctions between inflammatory fibroblasts marked by AKR1C1 or WNT5A in terms of cellular interactions and spatial co-localization patterns. Co-occurrence analysis reveals interferon-enriched community states including tertiary lymphoid structure (TLS) components, which exhibit differential rewiring between tumor, adjacent normal, and healthy normal tissues. The favorable response of interferon-enriched community states to immunotherapy is validated using immunotherapy-treated cancers (n=1,261) including our lung cancer cohort (n=497). Deconvolution of spatial transcriptomes discriminates TLS-enriched from non-enriched cell types among immunotherapy-favorable components. Our systematic dissection of tumor-normal ecosystems provides a deeper understanding of inter- and intra-tumoral heterogeneity.
2024-02-14 | GSE218989 | GEO
Project description:This model is based on:
Computational Modeling of the Crosstalk Between Macrophage Polarization and Tumor Cell Plasticity in the Tumor Microenvironment.
Abstract:
Tumor microenvironments contain multiple cell types interacting among one another via different signaling pathways. Furthermore, both cancer cells and different immune cells can display phenotypic plasticity in response to these communicating signals, thereby leading to complex spatiotemporal patterns that can impact therapeutic response. Here, we investigate the crosstalk between cancer cells and macrophages in a tumor microenvironment through in silico (computational) co-culture models. In particular, we investigate how macrophages of different polarization (M1 vs. M2) can interact with epithelial-mesenchymal plasticity of cancer cells, and conversely, how cancer cells exhibiting different phenotypes (epithelial vs. mesenchymal) can influence the polarization of macrophages. Based on interactions documented in the literature, an interaction network of cancer cells and macrophages is constructed. The steady states of the network are then analyzed. Various interactions were removed or added into the constructed-network to test the functions of those interactions. Also, parameters in the mathematical models were varied to explore their effects on the steady states of the network. In general, the interactions between cancer cells and macrophages can give rise to multiple stable steady-states for a given set of parameters and each steady state is stable against perturbations. Importantly, we show that the system can often reach one type of stable steady states where cancer cells go extinct. Our results may help inform efficient therapeutic strategies.
2019-09-23 | MODEL1909230002 | BioModels
Project description:Methods: To characterize the prostate cancer tumor microenvironment, we performed single-cell RNA-sequencing on prostate biopsies, prostatectomy specimens, and patient-derived organoids from localized prostate cancer patients. Results: We identify a population of tumor-associated club cells that could be associated with prostate carcinogenesis and uncover heterogeneous cellular states in prostate epithelial cells marked by high androgen signaling states that are enriched in prostate cancer. ERG- tumor cells, compared to ERG+ cells, demonstrate shared heterogeneity with surrounding luminal epithelial cells and appear to give rise to common tumor microenvironment responses. Finally, we show that prostate epithelial organoids recapitulate tumor-associated epithelial cell states and are enriched with distinct cell types and states from their parent tissues. Conclusions:Our results provide diagnostically relevant insights and advance our understanding of the cellular states associated with prostate carcinogenesis.
2021-08-23 | GSE176031 | GEO
Project description:These 95 arrays are the basis for Figure 2 of our manuscript "An interferon-response induced by tumor-stroma interaction in a subset of human breast cancers". Abstract:Background Communication between different cell types is a cardinal feature of multi-cellular organisms and perturbations in these cell-cell interactions are a key feature of cancer. However, little is known about the systematic effects of cell-cell interaction on global gene expression in cancer. Methods and Findings We used an ex vivo culture model to simulate tumor-stroma interaction by systematically co-cultivating breast cancer cells with stromal fibroblasts and determined associated gene expression changes with cDNA microarrays. The picture of heterotypic interaction effects that emerged from this analysis is complex, reflecting the variation in signaling capacities and responsiveness of the involved cells. A frequent and prominent response to epithelial-mesenchymal interaction was an induction of interferon-response genes, observed in 4 of the 7 breast cancer cell lines in response to co-culture with fibroblasts, but not in normal mammary epithelial cells. In response to close contact with these breast cancer cells, the fibroblasts secreted type I interferons, which, in turn, induced expression of the IRGs in the tumor cells. Immunohistochemical analysis of human breast cancer tissues showed that STAT1, the key transcriptional activator of the interferon-response genes, and itself an IRG, was expressed in a subset of the cancers, with a striking pattern of elevated expression in the cancer cells in contact with, or close proximity to, the tumor stroma ? paralleling the response seen in our ex vivo model. In vivo, expression of the interferon-response genes was remarkably coherent, providing a basis for segregation of the 295 early-stage breast cancers into two groups. Tumors with high expression levels (n=161) of IRG were associated with significantly shorter overall survival; 59 % at 10 years versus 80% for tumors with low interferon-response gene expression levels (n=134) (log-rank p=0.001). Conclusion Our results suggest that an interaction between some breast cancer cells and stromal fibroblasts can induce an interferon response, and that this response may be associated with a greater propensity for tumor progression. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Computed
2007-11-13 | E-GEOD-7260 | biostudies-arrayexpress
Project description:The solid tumor microenvironment is heterogeneous and varies in composition by tumor type. High-resolution profiling of the cell composition in tumor microenvironments is crucial to understanding its biological role and function in clinical outcomes. Previously, gene expression and DNA methylation-based deconvolution approaches for tumor microenvironment have succeeded in deconvolving major cell types. However, existing methods lack accuracy and specificity to tumor type and include a limited amount of cell types. We developed a novel DNA methylation-based algorithm, HiTIMED, to estimate cell proportions in tumor microenvironments with a high resolution. HiTIMED employs a tumor-site-specific hierarchical model to enhance the accuracy of the predictions. Seventeen cell types, three major tumor microenvironment components (tumor, immune, angiogenic), and twenty carcinoma types can be profiled by HiTIMED. We demonstrated prognostic significance of HiTIMED cell types that other methods in the tumor microenvironment deconvolution were not capturing. The high resolution of HiTIMED deconvolution provides additional opportunities to study the impact of the tumor microenvironment on clinically significant outcomes like immunotherapy response.
2022-11-16 | GSE193297 | GEO
Project description:Cancer-associated fibroblasts (CAFs), the principal components of tumor microenvironment, play multiple roles in breast cancer onset and progression. While their impact is widely accepted, treatment options to target CAFs in clinical practice were not yet well established. The nuclear receptor superfamily encompasses a druggable class of molecules, expressed in various stroma and parenchymal cell types, with the interesting therapeutic potential to modulate the reactive microenvironment. Having already addressed the oncosuppressive role of the nuclear Farnesoid X Receptor (FXR) in mammary epithelial cancer cells, the present study is aimed to assess the function of FXR in CAFs and evaluate whether its activation may affect their tumor-promoting features.
2018-12-31 | E-MTAB-6343 | biostudies-arrayexpress
Project description:Targeting autophagy in cancer cells and in the tumor microenvironment are current goals of cancer therapy. However, components of canonical autophagy play roles in other biological processes, adding complexity to this goal. One such alternative function of autophagy proteins is LC3-associated phagocytosis (LAP), which functions in phagosome maturation and subsequent signaling events. Here we show that impairment of LAP in the myeloid compartment, rather than canonical autophagy, induces control of tumor growth by tumor-associated macrophages (TAM) upon phagocytosis of dying tumor cells. Single cell RNAseq analysis revealed that defects in LAP induce pro-inflammatory gene expression and trigger STING-mediated type I interferon responses in TAM. We found that the anti-tumor effects of LAP impairment require tumor-infiltrating T cells, dependent upon the STING and the type I interferon response. Therefore, autophagy proteins in the myeloid cells of the tumor microenvironment contribute to immune suppression of T lymphocytes by effecting LAP.
2018-09-15 | GSE118019 | GEO
Project description:The tumor immune microenvironment is a main contributor to cancer progression and a promising therapeutic target for oncology. However, immune microenvironments vary profoundly between patients and biomarkers for prognosis and treatment response lack precision. A comprehensive compendium of tumor immune cells is required to pinpoint predictive cellular states and their spatial localization. We generated a single-cell resolved tumor immune cell atlas, jointly analyzing >500,000 cells from 217 patients and 13 cancer types, providing the basis for a patient stratification based on immune cell compositions. Projecting immune cells from external tumors onto the atlas facilitated an automated cell annotation system for a harmonized interpretation. To enable in situ mapping of immune populations for digital pathology, we developed SPOTlight, a computational tool that identified striking spatial immune cell patterns in tumor sections. We expect the atlas, together with our versatile toolbox for precision oncology, to advance currently applied stratification strategies for prognosis and immuno-therapy response.
2020-10-27 | GSE158803 | GEO
Project description:In mouse models of PDGF-driven glioma where Notch is tumor-suppressive, we find that Notch activity shapes interferon-response in tumor cells and the local immune microenvironment early during tumor progression. Notch inhibition disturbs cytokine expression by tumor cells, altering recruitment and activation of immune cell populations and favoring hyper-proliferative "immune niche" independent growth. Genetic inactivation of Notch in glioma cells also attenuates their response to interferon-gamma establishing a non-cell autonomous inhibitory feedback loop that further promotes immune evasion and aggressiveness. Hence, we propose that Notch signaling levels in tumor cells are key to orchestrate immune escape and microenvironment independency during brain tumor formation.
2022-07-07 | GSE160714 | GEO
Project description:Understanding the role of the immune microenvironment in modulating intratumor heterogeneity is essential for effective cancer therapies. Here we show that two types of tumor clonal landscapes emerge during early progression of prostate cancer in genetically-engineered mouse models. Using lineage tracing and single-cell transcriptomics, we find that slowly progressing tumors contain a multiclonal landscape of relatively homogenous subpopulations within a well-organized tumor microenvironment, whereas more advanced and aggressive tumors contain competing dominant and minor clones accompanied by a disordered microenvironment. We demonstrate that the dominant/minor modality is associated with differential immunoediting, in which minor clones are marked by increased expression of IFNγ-response genes and the T-cell activating chemokines Cxcl9 and Cxcl11. Furthermore, immunomodulation of the IFNγ pathway can rescue minor clones from elimination. These findings suggest new immunotherapy approaches to modulate clonal fitness and tumor progression in prostate cancer.
2023-04-01 | GSE196371 | GEO