AUTHOR=Chen Hao , Zhang Jianlin , Sun Xuehu , Wang Yao , Qian Yeben 

TITLE=Mitophagy-mediated molecular subtypes depict the hallmarks of the tumour metabolism and guide precision chemotherapy in pancreatic adenocarcinoma

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 10 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2022.901207

DOI=10.3389/fcell.2022.901207

ISSN=2296-634X

ABSTRACT=Abstract
Background: 
Mitophagy is tightly related to tumour occurrence and development. However, the heterogeneity of the tumour mitophagy landscape remains unexplored in pancreatic adenocarcinoma (PAAD).
Materials and Methods: 
We used Reactome database to retrieve and download the mitophagy-related, glycolysis-related and cholesterol biosynthesis-related signaling pathways.  Unsupervised clustering using the ‘ConsensusClusterPlus’ R package was performed to identify molecular subtypes related to mitophagy and metabolism. Prognosis-related mitophagy regulators were identified using univariate Cox regression analysis. Receiver operating characteristics and Kaplan–Meier survival analyses were established to test the diagnostic and prognostic role of the hub genes and prognosis risk model. Weighted gene co-expression network analysis (WGCNA) was utilized for screening the mitophagy subtype-related hub genes . Metascape was utilized to carry out functional enrichment analysis. The ‘glmnet’ R package was utilised to realise LASSO, and the ‘e1071’ R package was utilised for SVM. Chemotherapeutic drug sensitivity was estimated using the R package ‘pRRophetic’ and Genomics of Drug Sensitivity in Cancer database. The nomogram was established using the ‘rms’ R package.
Results: 
Three distinct mitophagy subtypes (low, high and intermediate) of PAAD were identified based on the landscape of mitophagy regulators. The high mitophagy subtype had the worst prognosis, highest mRNA expression-based stemness index scores and most hypoxic environment compared to the other subtypes. Additionally, glycolysis and cholesterol biosynthesis were significantly elevated. Three mitophagy subtype-specific gene signatures (CAST, CCDC6 and ERLIN1) were extracted using WGCNA and machine learning. Moreover, PAAD tumours were insensitive to conventional chemotherapy in the high mitophagy subtype and high CAST, CCDC6 and ERLIN1 expressed subtypes. Furthermore, CAST, CCDC6 and ERLIN1 affected immune cell infiltration (M1 and CD8Tcm), resulting in the altered prognosis of patients with PAAD. A nomogram was constructed to screen patients with the low mitophagy subtype, which showed a higher sensitivity to chemotherapeutic agents.
Conclusion: 
Based on various?bioinformatics?tools and databases, the PAAD heterogeneity regarding mitophagy was systematically examined. Three different PAAD subtypes having different outcomes, metabolism patterns and chemosensitivity were observed. Moreover, three novel biomarkers that are closely associated with mitophagy and have the potential to guide individualised treatment regimens in PAAD were obtained.