Dataset Information

Subpopulations of cancer-associated fibroblasts link the prognosis and metabolic features of pancreatic ductal adenocarcinoma.

ABSTRACT:

Background

Cancer-associated fibroblasts (CAFs) are a vital constituent of the tumor microenvironment (TME) and have several activities, but the effect of CAF heterogeneity on the molecular features and clinical outcomes of pancreatic ductal adenocarcinoma (PDAC) remains unknown.

Methods

An algorithm "scFrac" based on single-cell sequencing data from the Gene Expression Omnibus was introduced to emulate the enrichment of CAF subtypes in a TCGA-PDAC cohort and their prognostic influence, and confirmed by an external validation group (66 patients with PDAC) with multiplex immunohistochemistry staining. A comprehensive analysis including metabolic profile and transcription factor regulon activity was carried out among CAF subtypes.

Results

Three distinct CAF populations were confirmed: myofibroblast (myCAF), inflammatory CAF (iCAF), and antigen-presenting CAF (apCAF). These subtypes expressed distinct metabolic profiles and transcriptional regulon activity. KEGG pathway annotation demonstrated that complement and coagulation cascades, as well as cytokine-cytokine receptor interaction were dominant in iCAFs, and pathways related to focal adhesion, and ECM-receptor interaction showed dominance in myCAFs, while antigen processing and presentation were the top enriched pathways in apCAFs. iCAFs trended to glycolysis with CREB3L1, EGR2 and SOX4 activation, whereas myCAFs depend on the tricarboxylic acid cycle and its derivatives with NRF2, CEBPD and YBX1 activation. iCAF is a protective factor associated with an inflammatory phenotype, but myCAF is an important factor in the poor prognosis of PDAC.

Conclusions

We identified distinct molecular characteristics of 3 CAF subtypes in PDAC and plotted their metabolism profile. We introduced a novel algorism, scFrac, for exploring how CAF subgroups dysregulate cancer biology, and also shed a new therapeutic light on targeting the CAF subtype in TME.

SUBMITTER: Hu B

PROVIDER: S-EPMC8987890 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

Subpopulations of cancer-associated fibroblasts link the prognosis and metabolic features of pancreatic ductal adenocarcinoma.

Hu Beiyuan B Wu Chuntao C Mao Huarong H Gu Haitao H Dong Hanguang H Yan Jiuliang J Qi Zihao Z Yuan Lin L Dong Qiongzhu Q Long Jiang J

Annals of translational medicine 20220301 5

<h4>Background</h4>Cancer-associated fibroblasts (CAFs) are a vital constituent of the tumor microenvironment (TME) and have several activities, but the effect of CAF heterogeneity on the molecular features and clinical outcomes of pancreatic ductal adenocarcinoma (PDAC) remains unknown.<h4>Methods</h4>An algorithm "scFrac" based on single-cell sequencing data from the Gene Expression Omnibus was introduced to emulate the enrichment of CAF subtypes in a TCGA-PDAC cohort and their prognostic infl ...[more]

PMID: 35402584

Similar Datasets

Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors that lacks effective treatment options. Cancer-associated fibroblasts (CAFs), an important component of the tumor microenvironment, associated with tumor progression, prognosis, and treatment response. This work aimed to explore the novel CAFs-associated target to improve treatment strategies in PDAC.MethodsThe PDAC single-cell sequencing data (CRA001160, n = 35) were downloaded and integrated based on GSA databases to classify fibroblasts into fine subtypes. Functional enrichment analysis and coexpression regulatory network analysis were used to identify the functional phenotypes and biological properties of the different fibroblast subtypes. Fibroblast differentiation trajectories were constructed using pseudochronological analysis to identify initial and terminally differentiated subtypes of fibroblasts. The changes in the proportions of different fibroblast subtypes before and after PDAC immunotherapy were compared in responsive and nonresponding patients, and the relationships between fibroblast subtypes and PDAC immunotherapy responsiveness were determined based on GSA and GEO database. Using molecular biology methods to confirm the effects of BNIP3 on hypoxia and inflammation in CAFs. CAFs were co cultured with pancreatic cancer cells to detect their effects on migration and invasion of pancreatic cancer.ResultsSingle-cell data analysis divided fibroblasts into six subtypes. The differentiation trajectory suggested that BNIP3+ Fibro subtype exhibited terminal differentiation, and the expression of genes related to hypoxia and the inflammatory response increased gradually with differentiation time. The specific overexpressed genes in the BNIP3+ Fibro subtype were significantly associated with overall and disease progression-free survival in the patients with PDAC. Interestingly, the greater the proportion of the BNIP3+ Fibro subtype was, the worse the response of PDAC patients to immunotherapy, and the CRTL treatment regimen effectively reduced the proportion of the BNIP3+ Fibro subtype. After knocking out BNIP3, the hypoxia markers and inflammatory factors of CAFs were inhibited. Co-culture of CAFs with pancreatic cancer cells can increase the migration and invasion of pancreatic cancer, but this could be reversed by knocking out BNIP3.ConclusionsThis study revealed the BNIP3+ Fibro subtype associated with hypoxia and inflammatory responses, which was closely related to the poor prognosis of patients with PDAC, and identified signature genes that predict the immunotherapy response in PDAC.

Project description:IntroductionPancreatic ductal adenocarcinoma (PDAC) is projected to rise to the second leading cause of U.S. cancer-related deaths by 2020. Novel therapeutic targets are desperately needed. MicroRNAs (miRs) are small noncoding RNAs that function by suppressing gene expression and are dysregulated in cancer. miR-21 is overexpressed in PDAC tumor cells (TC) and is associated with decreased survival, chemoresistance and invasion. Dysregulation of miR regulatory networks in PDAC tumor-associated fibroblasts (TAFs) have not been previously described. In this study, we show that miR-21 expression in TAFs promotes TC invasion.MethodsIn-situ hybridization for miR-21 was performed on the 153 PDAC patient UCLA tissue microarray and 23 patient-matched lymph node metastases. Stromal and TC histoscores were correlated with clinicopathologic parameters by univariate and multivariate Cox regression. miR-21 positive cells were further characterized by immunofluorescence for mesenchymal/epithelial markers. For in vitro studies, TAFs were isolated from freshly resected human PDAC tumors by the outgrowth method. miR-21 was overexpressed/inhibited in fibroblasts and then co-cultured with GFP-MiaPaCa TCs to assess TC invasion in modified Boyden chambers.ResultsmiR-21 was upregulated in TAFs of 78% of tumors, and high miR-21 significantly correlated with decreased overall survival (P = 0.04). Stromal miR-21 expression was also significantly associated with lymph node invasion (P = 0.004), suggesting that it is driving TC spread. Co-immunofluorescence revealed that miR-21 colocalized with peritumoral fibroblasts expressing ?-smooth muscle actin. Moreover, expression of miR-21 in primary TAFs correlated with miR-21 in TAFs from patient-matched LN metastases; evidence that PDAC tumor cells induce TAFs to express miR-21. miR-21 expression in TAFs and TCs promotes invasion of TCs and is inhibited with anti-miR-21.ConclusionsmiR-21 expression in PDAC TAFs is associated with decreased overall survival and promotes TC invasion. Anti-miR-21 may represent a novel therapeutic strategy for dual targeting of both tumor and stroma in PDAC.

Project description:BackgroundPancreatic cancer is one of the most common malignancies worldwide. In recent years, specific metabolic activities, which involves the development of tumor, caused wide public concern. In this study, we wish to explore the correlation between metabolism and progression of tumor.MethodsA retrospective analysis including 95 patients with pancreatic ductal adenocarcinoma (PDAC) and PDAC patients from The Cancer Genome Atlas (TCGA), the International Cancer Genome Consortium (ICGC), and The Gene Expression Omnibus (GEO) database were involved in our study. Multivariate Cox regression analysis was used to construct the prognosis model. The potential connection between metabolism and immunity of PDAC was investigated through a weighted gene co-expression network analysis (WGCNA). 22 types of Tumor-infiltrating immune cells (TIICs) between high-risk and low-risk groups were estimated through CIBERSORT. Moreover, the potential immune-related signaling pathways between high-risk and low-risk groups were explored through the gene set enrichment analysis (GSEA). The role of key gene GMPS in developing pancreatic tumor was further investigated through CCK-8, colony-information, and Transwell.ResultsThe prognostic value of the MetS factors was analyzed using the Cox regression model, and a clinical MetS-based nomogram was established. Then, we established a metabolism-related signature to predict the prognosis of PDAC patients based on the TCGA databases and was validated in the ICGC database and the GEO database to find the distinct molecular mechanism of MetS genes in PDAC. The result of WGCNA showed that the blue module was associated with risk score, and genes in the blue module were found to be enriched in the immune-related signaling pathway. Furthermore, the result of CIBERSORT demonstrated that proportions of T cells CD8, T cells Regulatory, Tregs NK cells Activated, Dendritic cells Activated, and Mast cells Resting were different between high-risk and low-risk groups. These differences are potential causes of different prognoses of PDAC patients. GSEA and the protein-protein interaction network (PPI) further revealed that our metabolism-related signature was significantly enriched in immune-related biological processes. Moreover, knockdown of GMPS in PDAC cells suppressed proliferation, migration, and invasion of tumor cells, whereas overexpression of GMPS performed oppositely.ConclusionThe results shine light on fundamental mechanisms of metabolic genes on PDAC and establish a reliable and referable signature to evaluate the prognosis of PDAC. GMPS was identified as a potential candidate oncogene with in PDAC, which can be a novel biomarker and therapeutic target for PDAC treatment.

Project description:Purpose The present study aimed to clarify the distribution pattern of carcinoma associated fibroblasts (CAFs) across pancreatic ductal adenocarcinoma (PDAC) and its prognostic prediction value. Methods Data of two cohorts were retrospectively collected from consecutive patients who underwent primary pancreatic resection from January 2015 to December 2017. We used tumor specimens to screen out the most suitable markers for the spatial distribution analysis for CAFs subpopulations. We utilized a tissue microarray to assess the spatial intensity of α-SMA expression within the tumor microenvironment. Specifically, we classified CAFs into two types based on their α-SMA spatial expression. Type II CAFs were designated as those located in the juxtatumoural stroma with α-SMA expression that was moderate or higher, and those in the peripheral stroma with α-SMA expression that was less than moderate. All other cases, where the α-SMA expression did not meet these criteria, were categorized as Type I CAFs. Multivariable Cox proportional hazards regression was used to assess risk factors associated with patient outcomes. RNA sequencing data were obtained from bulk tumor samples and isolated CAFs from patients to reveal the distinct pattern and elucidated their fundamental characteristics. Results The α-SMA spatial intensity was the most suitable variable for representative of CAFs spatial characteristics. Patients with Type Ⅰ CAFs were more likely to be allocated into N1 or N2 of the N stage and Ⅱ and Ⅲ of the TNM stage. The spatial distribution pattern of CAFs (Type Ⅰ v.s. Type Ⅱ: HR, 1.568; 95 % CI, 1.053-2.334; P = 0.027) was an independent prognostic factor in the discovery cohort, so as in the validation (Type Ⅰ vs. Type Ⅱ: HR, 2.197; 95 % CI, 1.410-3.422; P = 0.001). RNA sequencing analysis revealed that the differentially expressed genes (DEGs) in Type I CAFs are closely associated with those in corresponding tumor tissues, highlighting the enhanced biological significance of immune-related and oncogenic invasive pathways. Conclusions Our findings that two types of α-SMA-positive CAFs with different spatial patterns present heterogeneously across tissues of PDACs and correlated with patients' outcomes. The spatial location of CAFs may facilitate patients' selection in precision medicine of PDACs.

Dataset Information

Subpopulations of cancer-associated fibroblasts link the prognosis and metabolic features of pancreatic ductal adenocarcinoma.

Background

Methods

Results

Conclusions

Publications

Subpopulations of cancer-associated fibroblasts link the prognosis and metabolic features of pancreatic ductal adenocarcinoma.

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