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Publications

Journal Article Epublish

PubMed: 40340806 DOI: 10.1186/s10020-025-01237-y

Transcriptome-wide analysis reveals potential roles of CFD and ANGPTL4 in fibroblasts regulating B cell lineage for extracellular matrix-driven clustering and novel avenues for immunotherapy in breast cancer.

Mol Med 31(1):179

Authors: Hongwei Wang, Yu-Nan Zhu, Sifan Zhang, Kexin Liu, Rong Huang, Zhigao Li, Lan Mei, Yingpu Li

Affiliations

  • Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, Heilongjiang Province, China.
  • Department of Neurobiology, Harbin Medical University, Harbin, 150081, Heilongjiang Province, China.
  • Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, Heilongjiang Province, China.
  • Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, Heilongjiang Province, China.
  • Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, Heilongjiang Province, China. NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang Province, China. Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province), College of Pharmacy, Harbin Medical University, Harbin, 150081, Heilongjiang Province, China.

Abstract

BACKGROUND

The remodeling of the extracellular matrix (ECM) plays a pivotal role in tumor progression and drug resistance. However, the compositional patterns of ECM in breast cancer and their underlying biological functions remain elusive.

METHODS

Transcriptome and genome data of breast cancer patients from TCGA database was downloaded. Patients were classified into different clusters by using non-negative matrix factorization (NMF) based on signatures of ECM components and regulators. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify core genes related to ECM clusters. Additional 10 independent public cohorts including Metabric, SCAN_B, GSE12276, GSE16446, GSE19615, GSE20685, GSE21653, GSE58644, GSE58812, and GSE88770 were collected to construct Training or Testing cohort, following machine learning calculating ECM correlated index (ECI) for survival analysis. Pathway enrichment and correlation analysis were used to explore the relationship among ECM clusters, ECI and TME. Single-cell transcriptome data from GSE161529 was processed for uncovering the differences among ECM clusters.

RESULTS

Using NMF, we identified three ECM clusters in the TCGA database: C1 (Neuron), C2 (ECM), and C3 (Immune). Subsequently, WGCNA was employed to pinpoint cluster-specific genes and develop a prognostic model. This model demonstrated robust predictive power for breast cancer patient survival in both the Training cohort (n = 5,392, AUC = 0.861) and the Testing cohort (n = 1,344, AUC = 0.711). Upon analyzing the tumor microenvironment (TME), we discovered that fibroblasts and B cell lineage were the core cell types associated with the ECM cluster phenotypes. Single-cell RNA sequencing data further revealed that angiopoietin like 4 (ANGPTL4) fibroblasts were specifically linked to the C2 phenotype, while complement factor D (CFD) fibroblasts characterized the other ECM clusters. CellChat analysis indicated that ANGPTL4 and CFD fibroblasts regulate B cell lineage via distinct signaling pathways. Additionally, analysis using the Kaplan-Meier Plotter website showed that CFD was favorable for immunotherapy response, whereas ANGPTL4 negatively impacted the outcomes of cancer patients receiving immunotherapy.

CONCLUSION

We identified distinct ECM clusters in breast cancer patients, irrespective of molecular subtypes. Additionally, we constructed an effective prognostic model based on these ECM clusters and recognized ANGPTL4 and CFD fibroblasts as potential biomarkers for immunotherapy in breast cancer.

MeSH

Cells, Genes, Cell Lineage, Breast Neoplasms, Molecular Biology, Complement Factor D, Transcriptome, Neoplasms, Phenotype, Immunotherapy, Breast, Cluster Analysis, Fibroblasts, Extracellular Matrix, B-Lymphocytes