Comprehensive Analysis of Bulk and Single-Cell Transcriptomic Data Reveals a Novel Signature Associated With Endoplasmic Reticulum Stress, Lipid Metabolism, and Liver Metastasis in Pancreatic Cancer

Authors

Xiaohong Liu
Bo Ren
Yuan Fang
Jie Ren
Xing Wang
Minzhi Gu
Feihan Zhou
Ruiling Xiao
Xiyuan Luo
Lei You
Yupei Zhao

Publication Date

4-29-2024

Journal

Journal of Translational Medicine

Abstract

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with high probability of recurrence and distant metastasis. Liver metastasis is the predominant metastatic mode developed in most pancreatic cancer cases, which seriously affects the overall survival rate of patients. Abnormally activated endoplasmic reticulum stress and lipid metabolism reprogramming are closely related to tumor growth and metastasis. This study aims to construct a prognostic model based on endoplasmic reticulum stress and lipid metabolism for pancreatic cancer, and further explore its correlation with tumor immunity and the possibility of immunotherapy.

METHODS: Transcriptomic and clinical data are acquired from TCGA, ICGC, and GEO databases. Potential prognostic genes were screened by consistent clustering and WGCNA methods, and the whole cohort was randomly divided into training and testing groups. The prognostic model was constructed by machine learning method in the training cohort and verified in the test, TCGA and ICGC cohorts. The clinical application of this model and its relationship with tumor immunity were analyzed, and the relationship between endoplasmic reticulum stress and intercellular communication was further explored.

RESULTS: A total of 92 characteristic genes related to endoplasmic reticulum stress, lipid metabolism and liver metastasis were identified in pancreatic cancer. We established and validated a prognostic model for pancreatic cancer with 7 signatures, including ADH1C, APOE, RAP1GAP, NPC1L1, P4HB, SOD2, and TNFSF10. This model is considered to be an independent prognosticator and is a more accurate predictor of overall survival than age, gender, and stage. TIDE score was increased in high-risk group, while the infiltration levels of CD8

CONCLUSIONS: We constructed and validated a novel prognostic model for pancreatic cancer, which can also be used as an instrumental variable to predict the prognosis and immune microenvironment. In addition, this study revealed the effect of ER stress on cell-cell communication in the tumor microenvironment.

Keywords

Humans, Endoplasmic Reticulum Stress, Pancreatic Neoplasms, Lipid Metabolism, Liver Neoplasms, Transcriptome, Single-Cell Analysis, Prognosis, Gene Expression Regulation, Neoplastic, Male, Female, Middle Aged, Gene Expression Profiling, Reproducibility of Results, Cohort Studies

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Supplementary Materials

PMID: 38685045