Revealing a cancer-associated fibroblast-based risk signature for pancreatic adenocarcinoma through single-cell and bulk RNA-seq analysis

Sep 27, 2024Aging

A cancer-related fibroblast gene pattern linked to pancreatic cancer risk identified from single-cell and bulk RNA analyses

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Four distinct clusters of cancer-associated fibroblasts (CAFs) were identified in pancreatic adenocarcinoma, with two associated with patient prognosis.

A seven-gene risk signature was developed based on differential gene expression analysis linked to CAF clusters.
This risk signature was found to be an independent predictor of outcomes in pancreatic adenocarcinoma.
The signature demonstrated predictive efficacy for immunotherapeutic responses.
A novel nomogram incorporating age and the risk signature showed strong reliability in predicting patient prognosis.
The risk signature correlated significantly with stromal and immune scores, as well as specific immune cell types.

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PURPOSE: Proliferation of stromal connective tissue is a hallmark of pancreatic adenocarcinoma (PAAD). The engagement of activated cancer-associated fibroblasts (CAFs) contributes to the progression of PAAD through their involvement in tumor fibrogenesis. However, the prognostic significance of CAF-based risk signature in PAAD has not been explored.

METHODS: The single-cell RNA sequencing (scRNA-seq) data sourced from GSE155698 within the Gene Expression Omnibus (GEO) database was supplemented by bulk RNA sequencing data from The Cancer Genome Atlas (TCGA) and microarray data retrieved from the GEO database. The scRNA-seq data underwent processing via the Seurat package to identify distinct CAF clusters utilizing specific CAF markers. Differential gene expression analysis between normal and tumor samples was conducted within the TCGA-PAAD cohort. Univariate Cox regression analysis pinpointed genes associated with CAF clusters, identifying prognostic CAF-related genes. These genes were utilized in LASSO regression to craft a predictive risk signature. Subsequently, integrating clinicopathological traits and the risk signature, a nomogram model was constructed.

RESULTS: Our scRNA-seq analysis unveiled four distinct CAF clusters in PAAD, with two linked to PAAD prognosis. Among 207 identified DEGs, 148 exhibited significant correlation with these CAF clusters, forming the basis of a seven-gene risk signature. This signature emerged as an independent predictor in multivariate analysis for PAAD and demonstrated predictive efficacy in immunotherapeutic outcomes. Additionally, a novel nomogram, integrating age and the CAF-based risk signature, exhibited robust predictability and reliability in prognosticating PAAD. Moreover, the risk signature displayed substantial correlations with stromal and immune scores, as well as specific immune cell types.

CONCLUSIONS: The prognosis of PAAD can be accurately predicted using the CAF-based risk signature, and a thorough analysis of the PAAD CAF signature may aid in deciphering the patient's immunotherapy response and presenting fresh cancer treatment options.

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Revealing a cancer-associated fibroblast-based risk signature for pancreatic adenocarcinoma through single-cell and bulk RNA-seq analysis

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