Discovery of a Linked Constellation of Gene Expression Revealed by Local Editing of Fibroblasts in Tumors
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE315708 | GEO | 2026/02/15
REPOSITORIES: GEO
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Project description:In the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) play a crucial role in promoting tumor progression by creating an immunosuppressive environment through cytokine secretion and antigen presentation. While previous studies have demonstrated that CAFs exhibit distinct metabolic profiles compared to normal fibroblasts, it remains unclear how these metabolic programs influence the immune landscape within tumors and which factors drive metabolic reprogramming in CAFs. Here, we found that glutamine synthesis by CAFs promotes the polarization of pro-tumorigenic tumor-associated macrophages (TAMs), and supports tumor growth by altering TAM composition, highlighting the pivotal role of CAFs in shaping the immunosuppressive TME. Mechanistically, we found that tumor-derived palmitic acid activates a signaling cascade involving Toll-like receptor 4 (TLR4), Syk, and NF-κB in fibroblasts, leading to inflammatory CAF polarization, and IL-6-induced glutamine synthesis. These findings uncover a novel metabolic symbiosis whereby tumor cells manipulate TAM polarization through CAF-mediated glutamine metabolism, presenting potential therapeutic targets for cancer immunotherapy.
2025-05-26 | GSE297727 | GEO
Project description:Cancer-associated fibroblasts (CAFs) are the dominant components of stroma in the tumor microenvironment (TME), and they influence cancer hallmarks by interacting with other TME components. However, the heterogeneity and dynamics of CAFs have not been systematically characterized across different cancer types. Here, we performed pan-cancer analysis on 226 samples from 164 donors across 10 types of solid cancers to profile the TME at single-cell resolution. The activation trajectory of fibroblasts into various major types of CAFs was divided into three distinct differentiated states and was capable of sculpting the TME, which was associated with the prognosis of immunotherapy. On the other hand, except for activation, minor CAF components represented the dynamic transition between fibroblasts and other TME components (i.e., macrophages, peripheral nerve and endothelial cells) and delineated the alternative origins of CAFs. Particularly, the ubiquitous presentation of CAFEndoMT (endothelial-mesenchymal transition), which may be stimulated by proximal SPP1+ tumor-associated macrophages, played a role in angiogenesis and patient survival stratifications. Our study comprehensively profiled the heterogeneity and plasticity of CAFs, implied a potential divergent origin of different CAF populations, and highlighted its generalized key role in the TME across different cancer types.
2022-08-07 | GSE210347 | GEO
Project description:The pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β) are expressed simultaneously and have tumor-promoting roles in breast cancer. In parallel, mesenchymal stem cells (MSCs) undergo transition at the tumor site to cancer-associated fibroblasts (CAFs), which are generally connected to enhanced tumor progression. Here, we determined the impact of consistent inflammatory stimulation on stromal cell plasticity. MSCs that were persistently stimulated by TNFα+IL-1β (2-3 weeks) gained a CAF-like morphology, accompanied by prominent changes in gene expression, including in stroma/fibroblast-related genes. These CAF-like cells expressed elevated levels of vimentin and fibroblast activation protein (FAP) and demonstrated significantly increased ability to contract collagen gels. Moreover, they have gained the phenotype of inflammatory CAFs, as indicated by reduced expression of α smooth muscle actin (αSMA), increased proliferation and elevated expression of inflammatory genes and proteins, primarily inflammatory chemokines. These inflammatory CAFs released factors that enhanced tumor cell detachment, spreading and migration; the inflammatory CAF-derived factors elevated cancer cell migration by stimulating the chemokine receptors CCR2, CCR5 and CXCR1/2 and Ras-activating receptors, expressed by the cancer cells. Together, these novel findings demonstrate that chronic inflammation, per se, can induce MSC-to-CAF transition, leading to generation of tumor-promoting inflammatory CAFs.
2021-08-10 | PXD022635 | Pride
Project description:Cancer-associated fibroblasts (CAFs) represent a central population of the tumor microenvironment (TME). Recently, single-cell RNA sequencing (scRNA-seq) analyes of primary tumors of different cancer entities yielded different classifications of CAF subsets underscoring heterogeneity of CAFs within the TME. Here, we analyzed the transcriptional signatures of approximately 8,400 CAFs and normal fibroblasts by scRNA-seq and compared genetic profiles of CAFs from murine melanoma primary tumors to CAFs from corresponding melanoma lung metastases. This revealed distinct subsets for primary tumor and metastasis specific CAF populations, respectively. Combined with spatial characterization of metastasis CAFs at the RNA and protein level, scRNA-analyses indicate a tumor-dependent crosstalk between neutrophils and CAFs, mediated via SAA3 and IL1b related signaling pathways, which can be recapitulated in vitro. Importantly, analyzing tissue sections of human patient samples this link was found to be present in human melanoma metastasis. Taken together, our data highlights unique characteristics of metastasis CAFs with potential therapeutic impact for melanoma metastasis.
2025-01-01 | GSE254072 | GEO
Project description:Introduction: Malignant pleural mesothelioma (MPM) is an aggressive malignancy with poor prognosis. Unlike many other cancers, MPM is mostly characterized by inactivation of tumor suppressor genes. Its highly malignant nature in absence of tumor driving oncogene mutations indicates an extrinsic supply of stimulating signals by cells of the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are an abundant cell type of the TME and have been shown to drive the progression of several cancer types. The aim of the current study was to isolate and characterize patient-derived mesothelioma-associated fibroblasts (Meso-CAFs), and evaluate their impact on MPM cells. Methods: Meso-CAFs were isolated from surgical specimens of MPM patients and analyzed by comparative genomic hybridization, transcriptomics and proteomics. Human MPM cell lines were retrovirally transduced with GFP. The impact of Meso-CAFs on tumor cell growth, migration, and response to pathway inhibitors and cisplatin was investigated in 2D and 3D co-culture models by videomicroscopy and automated image analysis. Results: Meso-CAFs possess normal genomes without gene copy number aberrations typical for MPM cells. They express CAF markers and lack MPM marker expression. Their proteome and secretome profiles clearly differ from normal lung fibroblasts with particularly strong differences in the fraction of actively secreted proteins. The presence of Meso-CAFs in co-culture resulted in increased proliferation and migration of MPM cells. A similar effect on cell growth was induced by conditioned medium. Met/PI3K or WNT signaling inhibition abolished the Meso-CAF-mediated growth stimulation. While Meso-CAFs reduced the efficacy of EGFR inhibition in co-cultures, they did not provide protection of tumor cells against cisplatin. Conclusion: Our study provides the first characterization of human patient-derived Meso-CAFs and demonstrates a strong impact of Meso-CAFs on tumor cell growth and migration, two key aspects of MPM aggressiveness, indicating a substantial role of Meso-CAFs in driving MPM progression. Moreover, we show that Meso-CAFs significantly influence drug response and identify signaling pathways required for Meso-CAF-mediated growth stimulation. These data could be relevant for improving therapeutic strategies in MPM.
2023-06-20 | PXD035987 | Pride
Project description:Introduction: Malignant pleural mesothelioma (MPM) is an aggressive malignancy with poor prognosis. Unlike many other cancers, MPM is mostly characterized by inactivation of tumor suppressor genes. Its highly malignant nature in absence of tumor driving oncogene mutations indicates an extrinsic supply of stimulating signals by cells of the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are an abundant cell type of the TME and have been shown to drive the progression of several cancer types. The aim of the current study was to isolate and characterize patient-derived mesothelioma-associated fibroblasts (Meso-CAFs), and evaluate their impact on MPM cells. Methods: Meso-CAFs were isolated from surgical specimens of MPM patients and analyzed by comparative genomic hybridization, transcriptomics and proteomics. Human MPM cell lines were retrovirally transduced with GFP. The impact of Meso-CAFs on tumor cell growth, migration, and response to pathway inhibitors and cisplatin was investigated in 2D and 3D co-culture models by videomicroscopy and automated image analysis. Results: Meso-CAFs possess normal genomes without gene copy number aberrations typical for MPM cells. They express CAF markers and lack MPM marker expression. Their proteome and secretome profiles clearly differ from normal lung fibroblasts with particularly strong differences in the fraction of actively secreted proteins. The presence of Meso-CAFs in co-culture resulted in increased proliferation and migration of MPM cells. A similar effect on cell growth was induced by conditioned medium. Met/PI3K or WNT signaling inhibition abolished the Meso-CAF-mediated growth stimulation. While Meso-CAFs reduced the efficacy of EGFR inhibition in co-cultures, they did not provide protection of tumor cells against cisplatin. Conclusion: Our study provides the first characterization of human patient-derived Meso-CAFs and demonstrates a strong impact of Meso-CAFs on tumor cell growth and migration, two key aspects of MPM aggressiveness, indicating a substantial role of Meso-CAFs in driving MPM progression. Moreover, we show that Meso-CAFs significantly influence drug response and identify signaling pathways required for Meso-CAF-mediated growth stimulation. These data could be relevant for improving therapeutic strategies in MPM.
2023-06-19 | PXD036127 | Pride
Project description:Introduction: Malignant pleural mesothelioma (MPM) is an aggressive malignancy with poor prognosis. Unlike many other cancers, MPM is mostly characterized by inactivation of tumor suppressor genes. Its highly malignant nature in absence of tumor driving oncogene mutations indicates an extrinsic supply of stimulating signals by cells of the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are an abundant cell type of the TME and have been shown to drive the progression of several cancer types. The aim of the current study was to isolate and characterize patient-derived mesothelioma-associated fibroblasts (Meso-CAFs), and evaluate their impact on MPM cells. Methods: Meso-CAFs were isolated from surgical specimens of MPM patients and analyzed by comparative genomic hybridization, transcriptomics and proteomics. Human MPM cell lines were retrovirally transduced with GFP. The impact of Meso-CAFs on tumor cell growth, migration, and response to pathway inhibitors and cisplatin was investigated in 2D and 3D co-culture models by videomicroscopy and automated image analysis. Results: Meso-CAFs possess normal genomes without gene copy number aberrations typical for MPM cells. They express CAF markers and lack MPM marker expression. Their proteome and secretome profiles clearly differ from normal lung fibroblasts with particularly strong differences in the fraction of actively secreted proteins. The presence of Meso-CAFs in co-culture resulted in increased proliferation and migration of MPM cells. A similar effect on cell growth was induced by conditioned medium. Met/PI3K or WNT signaling inhibition abolished the Meso-CAF-mediated growth stimulation. While Meso-CAFs reduced the efficacy of EGFR inhibition in co-cultures, they did not provide protection of tumor cells against cisplatin. Conclusion: Our study provides the first characterization of human patient-derived Meso-CAFs and demonstrates a strong impact of Meso-CAFs on tumor cell growth and migration, two key aspects of MPM aggressiveness, indicating a substantial role of Meso-CAFs in driving MPM progression. Moreover, we show that Meso-CAFs significantly influence drug response and identify signaling pathways required for Meso-CAF-mediated growth stimulation. These data could be relevant for improving therapeutic strategies in MPM.
2023-06-20 | PXD036017 | Pride
Project description:Cancer-associated fibroblasts (CAFs) are one of the components in tumor microenvironment (TME) that can facilitate tumor progression, invasion, and metastasis directly through tumor-CAF interactions, or indirectly by crosstalking with tumor infiltrating immune cells and inducing immunosuppressive TME. Indeed, high stromal signature has been associated with reduced therapeutic efficacy and resistance to Immune Checkpoint Blockade. AEBP1 is highly expressed in myofibroblast cells whose expression is further upregulated in activated fibroblasts and the extracellular matrix (ECM)-producing CAFs. AEBP1 has two alternatively spliced isoforms that the extracellular isoform binds to collagen and promotes collagen remodeling, and the intracellular isoform modulates transcription and signaling. We observed expression of both isoforms of AEBP1 in primary human CAFs. Our data showed that combined knock out (KO) of both isoforms of AEBP1 by gene editing technology decreased CAF proliferation, collagen gel contractility and CAF-mediated tumor cell proliferation in vitro. Pan AEBP1 KO mouse fibroblasts also showed reduced activity in vitro and in vivo in the co-implantation mouse model. We found that knocking out both isoforms of AEBP1 downregulated the collagen biosynthesis and ECM organization related pathways in both mouse fibroblasts and primary human CAFs through RNA sequencing studies. In addition, loss of AEBP1 in fibroblasts impacted tumor cell phenotypes resulting in significant decrease of tumor cells with,with epithelial-mesenchymal transition signature in the co-implantation mouse model. Furthermore, AEBP1 KO in CAFs enhanced the anti-PD-1 induced effector T cell activity and the anti-PD-1 efficacy in this co-implantation model. Altogether, our results demonstrate that AEBP1 is important in regulating CAF function in the TME. Inhibiting AEBP1, therefore, may be a novel strategy in targeting CAF tumor-supporting activity and overcoming cancer resistance to anti-PD-1 immunotherapy.
2025-09-30 | GSE308848 | GEO
Project description:Cancer-associated fibroblasts (CAFs) are one of the components in tumor microenvironment (TME) that can facilitate tumor progression, invasion, and metastasis directly through tumor-CAF interactions, or indirectly by crosstalking with tumor infiltrating immune cells and inducing immunosuppressive TME. Indeed, high stromal signature has been associated with reduced therapeutic efficacy and resistance to Immune Checkpoint Blockade. AEBP1 is highly expressed in myofibroblast cells whose expression is further upregulated in activated fibroblasts and the extracellular matrix (ECM)-producing CAFs. AEBP1 has two alternatively spliced isoforms that the extracellular isoform binds to collagen and promotes collagen remodeling, and the intracellular isoform modulates transcription and signaling. We observed expression of both isoforms of AEBP1 in primary human CAFs. Our data showed that combined knock out (KO) of both isoforms of AEBP1 by gene editing technology decreased CAF proliferation, collagen gel contractility and CAF-mediated tumor cell proliferation in vitro. Pan AEBP1 KO mouse fibroblasts also showed reduced activity in vitro and in vivo in the co-implantation mouse model. We found that knocking out both isoforms of AEBP1 downregulated the collagen biosynthesis and ECM organization related pathways in both mouse fibroblasts and primary human CAFs through RNA sequencing studies. In addition, loss of AEBP1 in fibroblasts impacted tumor cell phenotypes resulting in significant decrease of tumor cells with,with epithelial-mesenchymal transition signature in the co-implantation mouse model. Furthermore, AEBP1 KO in CAFs enhanced the anti-PD-1 induced effector T cell activity and the anti-PD-1 efficacy in this co-implantation model. Altogether, our results demonstrate that AEBP1 is important in regulating CAF function in the TME. Inhibiting AEBP1, therefore, may be a novel strategy in targeting CAF tumor-supporting activity and overcoming cancer resistance to anti-PD-1 immunotherapy.
2025-06-28 | GSE301078 | GEO
Project description:Tumor microenvironment coevolves with and simultaneously sustains cancer progression. Reactive fibroblasts found in prostate cancer (PCa), known as cancer associated fibroblasts (CAF), have been indeed shown to fuel tumor development and metastasis by mutually interacting with PCa cells. Little is known about the molecular mechanisms that lead to activation of CAFs from tissue-resident fibroblasts, circulating marrow-derived fibroblast progenitors or mesenchymal stem cells. Through integrated gene and microRNA expression profiling, here we showed that transcriptome of CAFs isolated from prostate tumors strictly resembles that of normal fibroblasts stimulated in vitro with interleukin-6 (IL6), thus confirming the capability of the cytokine to promote acquisition of an activated and cancer-promoting phenotype, and, for the first time, proving that IL6 is able per se to induce all the complex transcriptional changes characteristic of patient-derived CAFs. Comparison with publicly available datasets, however, suggested that prostate CAFs may be alternatively characterized by IL6 and TGF?-related signatures, indicating that either signal, depending on the context, tumor stage and etiology, may concur to fibroblast activation. Our analyses also highlighted pathways relevant for induction of reactive stroma, including genes the role of which in fibroblast activation is still to be explored. In addition, we revealed a role for muscle-specific miR-133b as a soluble factor secreted by activated fibroblasts to support paracrine activation of non-activated fibroblasts or promote tumor progression. Overall, in this study we provided insights on the molecular mechanisms driving fibroblast activation in prostate cancer, thus contributing to identify novel hits for the development of therapeutic strategies targeting the crucial interplay between tumor cells and their microenvironment. Tumor microenvironment coevolves with and simultaneously sustains cancer progression. Reactive fibroblasts found in prostate cancer (PCa), known as cancer associated fibroblasts (CAF), have been indeed shown to fuel tumor development and metastasis by mutually interacting with PCa cells. Little is known about the molecular mechanisms that lead to activation of CAFs from tissue-resident fibroblasts, circulating marrow-derived fibroblast progenitors or mesenchymal stem cells. Through integrated gene and microRNA expression profiling, here we showed that transcriptome of CAFs isolated from prostate tumors strictly resembles that of normal fibroblasts stimulated in vitro with interleukin-6 (IL6), thus confirming the capability of the cytokine to promote acquisition of an activated and cancer-promoting phenotype, and, for the first time, proving that IL6 is able per se to induce all the complex transcriptional changes characteristic of patient-derived CAFs. Comparison with publicly available datasets, however, suggested that prostate CAFs may be alternatively characterized by IL6 and TGF?-related signatures, indicating that either signal, depending on the context, tumor stage and etiology, may concur to fibroblast activation. Our analyses also highlighted pathways relevant for induction of reactive stroma, including genes the role of which in fibroblast activation is still to be explored. In addition, we revealed a role for muscle-specific miR-133b as a soluble factor secreted by activated fibroblasts to support paracrine activation of non-activated fibroblasts or promote tumor progression. Overall, in this study we provided insights on the molecular mechanisms driving fibroblast activation in prostate cancer, thus contributing to identify novel hits for the development of therapeutic strategies targeting the crucial interplay between tumor cells and their microenvironment. Tumor microenvironment coevolves with and simultaneously sustains cancer progression. Reactive fibroblasts found in prostate cancer (PCa), known as cancer associated fibroblasts (CAF), have been indeed shown to fuel tumor development and metastasis by mutually interacting with PCa cells. Little is known about the molecular mechanisms that lead to activation of CAFs from tissue-resident fibroblasts, circulating marrow-derived fibroblast progenitors or mesenchymal stem cells. Through integrated gene and microRNA expression profiling, here we showed that transcriptome of CAFs isolated from prostate tumors strictly resembles that of normal fibroblasts stimulated in vitro with interleukin-6 (IL6), thus confirming the capability of the cytokine to promote acquisition of an activated and cancer-promoting phenotype, and, for the first time, proving that IL6 is able per se to induce all the complex transcriptional changes characteristic of patient-derived CAFs. Comparison with publicly available datasets, however, suggested that prostate CAFs may be alternatively characterized by IL6 and TGF?-related signatures, indicating that either signal, depending on the context, tumor stage and etiology, may concur to fibroblast activation. Our analyses also highlighted pathways relevant for induction of reactive stroma, including genes the role of which in fibroblast activation is still to be explored. In addition, we revealed a role for muscle-specific miR-133b as a soluble factor secreted by activated fibroblasts to support paracrine activation of non-activated fibroblasts or promote tumor progression. Overall, in this study we provided insights on the molecular mechanisms driving fibroblast activation in prostate cancer, thus contributing to identify novel hits for the development of therapeutic strategies targeting the crucial interplay between tumor cells and their microenvironment. In the present study, patient derived-CAFs and HPFs activated in vitro with either TGF? or IL6 were comparatively analyzed for gene and microRNA (miRNA) expression profiles, with the aim to define transcriptional pathways responsible for fibroblast activation and establish whether different subpopulations of CAFs may exist in PCa.
2015-09-01 | E-GEOD-68164 | biostudies-arrayexpress