Tumor-produced and aging-associated oncometabolite, methylmalonic acid, promotes cancer-associated fibroblast activation to drive metastatic progression
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE190929 | GEO | 2022/10/04
REPOSITORIES: GEO
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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 TGFβ-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 TGFβ-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 TGFβ-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 TGFβ 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-68165 | biostudies-arrayexpress
Project description:Introduction: Oral squamous cell carcinoma (OSCC) is the most common form of head and neck cancer and has a survival rate of ~50% over five years. New treatment strategies are sorely needed to improve survival rates – and a better understanding of the mechanisms underlying tumorigenesis is needed to develop these strategies. The role of the tumor microenvironment (TME) has increasingly been identified as crucial in tumor progression and metastasis. One of the main constituents of the TME, cancer-associated fibroblasts (CAFs), plays a key role in influencing the biological behavior of tumors. Multiple mechanisms contribute to CAF activation, such as TGFβ signaling, but the role of extracellular vesicles (EVs) in CAF activation in OSCC is poorly understood. Assessing the impact of oral cancer-derived EVs on CAF activation will help to better illuminate OSCC pathophysiology and may drive development of novel treatments options. Materials and Methods: EVs were isolated from OSCC cell lines (Cal 27, SCC-9, SCC-25) using differential centrifugation. Nanoparticle tracking analysis was used for EV quantification and size characterization, and Western blot to confirm the presence of EV protein markers. Oral fibroblasts were co-cultured with enriched EVs, TGFβ, or PBS over 72 hours to assess activation. Flow cytometry was used to evaluate the difference in CAF markers. RNA collected from fibroblasts was extracted and the transcriptome was sequenced. Conditioned media from the co-cultures was evaluated with cytokine array profiling. Results: OSCC-derived EVs can activate oral fibroblasts into CAFs that are different from those activated by TGFβ, suggesting different mechanisms of activation and different functional properties. Gene set enrichment analysis using expression data from activated CAFs showed several upregulated inflammatory pathways in those CAFs exposed to OSCC-derived EVs. Marker genes for inflammatory CAF subtypes were also upregulated. This was not seen in CAFs activated by TGFβ. Finally, cytokine array analysis on secreted proteins from CAFs revealed elevated levels of several pro-inflammatory cytokines from CAFs activated by EVs, for instance IL-8 and CXCL5. Conclusions: Taken together, our results reveal the ability of OSCC-derived EVs to activate fibroblasts into CAFs. These CAFs seem to have unique properties, differing from TGFβ-activated CAFs. Gaining an understanding of the interplay between EVs and stromal cells such as CAFs could lead to further insights into OSCC tumorigenesis and potential novel therapeutics.
2023-09-07 | GSE233618 | GEO
Project description:Extracellular vesicles (EVs) participate in cell-stroma crosstalk within tumor microenvironment (TME) and Fb are key elements that contribute to tumor promotion. In thyroid cancer, the most prevalent endocrine malignancy, the relevance of Fb in the TME and EVs is beginning to be deciphered. Using an in vitro model of tumor-stroma crosstalk, we performed the comparative proteomic analysis of EVs secreted in tumoral- and non-tumoral milieu to describe EV-functionality and examine their possible role in thyroid tumor progression-related events. Tumor (TPC-1, 8505c) or non-tumor (NThyOri) thyroid cells were co-cultured with human fibroblasts (Fb). EVs, obtained by ultracentrifugation of conditioned media (CMs), were characterized by mass-spectrometry.
2022-08-02 | PXD028081 | Pride
Project description: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.
2022-12-31 | E-MTAB-12179 | biostudies-arrayexpress
Project description:Biliary fibrosis has the effect on biliary tract contribution to cholangiocarcinoma (CCA). Activated myofibroblast accompanying cancer-associated fibroblasts (CAFs) are the abundant in tumor stroma of CCA development and plays an important for tumor microenvironment. Although Helicobacter pylori infection is known risk for CCA, the interaction of CAFs and H. pylori is unclear. This study aimed to demonstrate the effect of H. pylori on the tumorigenesis and progression of the CAFs cell in vitro.
2024-05-10 | PXD042124 | JPOST Repository
Project description:Ovarian cancer is the most lethal malignancy in the United States. In the year 2012, there will be an estimated 22,280 new cases and 15,500 deaths from ovarian cancer in the country (Siegel et al., 2012). While studies on ovarian cancer pathogenesis were mainly focused on the epithelial component of the tumor, understanding in the role of cancer associated fibroblasts (CAFs) in ovarian cancer progression is limited. We hypothesized that comparing the gene expression profiles of different components from laser capture microdissected ovarian tissue will allow us to identify an ovarian CAFs specific gene signature which accounts for the supportive role of CAFs in ovarian cancer progression. In this study, gene expression profiling was completed for 31 cancer stroma samples and 32 samples of epithelial component from high grade serous ovarian cancer patients. 8 microdissected normal ovarian stroma and 6 normal human ovarian surface epithelium (HOSE) samples were also included in the study. By comparing the expression data from cancer stroma against that from normal stroma, cancer cells and HOSE, we identified a set of differential expressed genes in ovarian CAFs which showed correlation with cancer patient survival. Further study on these genes can reveal their roles in ovarian cancer progression and pathogenesis. Ultimately, ovarian CAFs specified genes identified in this study may aid in the classification and enhancement of patient outcome. Transcriptome profiling analyses were performed on 31 laser microdissected cancer associated stroma samples, 32 epithelial tumor samples from high grade serous ovarian cancer patients, 8 microdissected normal ovarian stroma samples and 6 ovarian surface epthelium (HOSE) samples using the Affymetrix human genome U133 Plus 2.0 microarray.
2014-09-11 | E-GEOD-40595 | biostudies-arrayexpress
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:Gastric cancer is the 3rd most lethal cancer worldwide, and the genomic status of its cancer cells has not translated into effective prognostic or therapeutic strategies. We therefore hypothesize that outcomes may depend on the tumor microenvironment (TME), and in particular cancer-associated fibroblasts (CAFs). However, very little is known about the role of CAFs in gastric cancer. To address this, we map the transcriptional landscape of human gastric cancer stroma by microdissection and RNA sequencing of CAFs from gastric cancer patients. We find a stromal gene signature associated with poor disease outcome. This signature is regulated by the transcription factor Heat Shock Factor 1 (HSF1), that activates CAF-derived extracellular vesicles (EVs) that transfer components including Inhibin Subunit Beta A (INHBA) and Thrombospondin 2 (THBS2), to the TME to promote cancer. Together, our work provides the first transcriptional map of human gastric cancer stroma, and highlights HSF1 and its transcriptional targets as potential diagnostic and therapeutic targets in the genomically stable tumor microenvironment.
2021-02-28 | GSE165211 | GEO
Project description:Gastric cancer is the 3rd most lethal cancer worldwide, and the genomic status of its cancer cells has not translated into effective prognostic or therapeutic strategies. We therefore hypothesize that outcomes may depend on the tumor microenvironment (TME), and in particular cancer-associated fibroblasts (CAFs). However, very little is known about the role of CAFs in gastric cancer. To address this, we map the transcriptional landscape of human gastric cancer stroma by microdissection and RNA sequencing of CAFs from gastric cancer patients. We find a stromal gene signature associated with poor disease outcome. This signature is regulated by the transcription factor Heat Shock Factor 1 (HSF1), that activates CAF-derived extracellular vesicles (EVs) that transfer components including Inhibin Subunit Beta A (INHBA) and Thrombospondin 2 (THBS2), to the TME to promote cancer. Together, our work provides the first transcriptional map of human gastric cancer stroma, and highlights HSF1 and its transcriptional targets as potential diagnostic and therapeutic targets in the genomically stable tumor microenvironment.
2021-02-28 | GSE162301 | GEO
Project description:With the advent of cancer immunotherapy, intense investigation has been focused on tumor-infiltrating immune cells. With only a fraction of patients responding to these new therapies, a better understanding of all elements of the tumor microenvironment (TME) that may influence therapeutic outcome is needed. Stromal elements of the TME, chiefly fibroblasts, have emerged as potential contributors to tumor progression and most recently resistance to immunotherapy, but their precise composition and clinical relevance remain incompletely understood. Here we use single-cell transcriptomics to chart the fibroblastic landscape during pancreatic ductal adenocarcinoma (PDAC) progression in animal models, identifying two healthy tissue fibroblast subsets that co-evolve along individual trajectories into four subsets of carcinoma-associated fibroblasts (CAFs).
2019-10-31 | E-MTAB-8483 | biostudies-arrayexpress