» Articles » PMID: 39487387

Integrated Bulk and Single-cell Profiling Characterize Sphingolipid Metabolism in Pancreatic Cancer

Overview
Journal BMC Cancer
Publisher Biomed Central
Specialty Oncology
Date 2024 Nov 2
PMID 39487387
Authors
Affiliations
Soon will be listed here.
Abstract

Background: Abnormal sphingolipid metabolism (SM) is closely linked to the incidence of cancers. However, the role of SM in pancreatic cancer (PC) remains unclear. This study aims to explore the significance of SM in the prognosis, immune microenvironment, and treatment of PC.

Methods: Single-cell and bulk transcriptome data of PC were acquired via TCGA and GEO databases. SM-related genes (SMRGs) were obtained via MSigDB database. Consensus clustering was utilized to construct SM-related molecular subtypes. LASSO and Cox regression were utilized to build SM-related prognostic signature. ESTIMATE and CIBERSORT algorithms were employed to assess the tumour immune microenvironment. OncoPredict package was used to predict drug sensitivity. CCK-8, scratch, and transwell experiments were performed to analyze the function of ANKRD22 in PC cell line PANC-1 and BxPC-3.

Results: A total of 153 SMRGs were acquired, of which 48 were linked to PC patients' prognosis. Two SM-related subtypes (SMRGcluster A and B) were identified in PC. SMRGcluster A had a poorer outcome and more active SM process compared to SMRGcluster B. Immune analysis revealed that SMRGcluster B had higher immune and stromal scores and CD8 + T cell abundance, while SMRGcluster A had a higher tumour purity score and M0 macrophages and activated dendritic cell abundance. PC with SMRGcluster B was more susceptible to gemcitabine, paclitaxel, and oxaliplatin. Then SM-related prognostic model (including ANLN, ANKRD22, and DKK1) was built, which had a very good predictive performance. Single-cell analysis revealed that in PC microenvironment, macrophages, epithelial cells, and endothelial cells had relatively higher SM activity. ANKRD22, DKK1, and ANLN have relatively higher expression levels in epithelial cells. Cell subpopulations with high expression of ANKRD22, DKK1, and ANLN had more active SM activity. In vitro experiments showed that ANKRD22 knockdown can inhibit the proliferation, migration, and invasion of PC cells.

Conclusion: This study revealed the important significance of SM in PC and identified SM-associated molecular subtypes and prognostic model, which provided novel perspectives on the stratification, prognostic prediction, and precision treatment of PC patients.

Citing Articles

Development and functional validation of a disulfidoptosis-related gene prognostic model for lung adenocarcinoma based on bioinformatics and experimental validation.

Shen T, Lu Z, Yang S, Zhang D, Ke Y, Chen Z Front Immunol. 2025; 16:1540578.

PMID: 39995671 PMC: 11847864. DOI: 10.3389/fimmu.2025.1540578.

References
1.
Qiu Y, Yang S, Pan T, Yu L, Liu J, Zhu Y . ANKRD22 is involved in the progression of prostate cancer. Oncol Lett. 2019; 18(4):4106-4113. PMC: 6732940. DOI: 10.3892/ol.2019.10738. View

2.
Yoshihara K, Shahmoradgoli M, Martinez E, Vegesna R, Kim H, Torres-Garcia W . Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013; 4:2612. PMC: 3826632. DOI: 10.1038/ncomms3612. View

3.
Yang H, Li Z, Zhu S, Wang W, Zhang J, Zhao D . Molecular mechanisms of pancreatic cancer liver metastasis: the role of PAK2. Front Immunol. 2024; 15:1347683. PMC: 10853442. DOI: 10.3389/fimmu.2024.1347683. View

4.
Ruckhaberle E, Rody A, Engels K, Gaetje R, von Minckwitz G, Schiffmann S . Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer. Breast Cancer Res Treat. 2007; 112(1):41-52. DOI: 10.1007/s10549-007-9836-9. View

5.
Leek J, Johnson W, Parker H, Jaffe A, Storey J . The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics. 2012; 28(6):882-3. PMC: 3307112. DOI: 10.1093/bioinformatics/bts034. View