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Intratumoral disulfidptosis heterogeneity in triple-negative breast cancer, a multiomics integration analysis
Zi-Xian Dong1, Yang Ou-Yang2, Lan Fang3,4
1Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, China.
Background:
Triple-negative breast cancer (TNBC) is characterized by heterogeneity and metabolic reprogramming. Disulfidptosis represents a new category of regulated cell death that is mediated by cystine and cysteine metabolism. However, the underlying mechanism related to the heterogeneity of TNBC disulfidptosis remains unclear. In this study, we aimed to analyze whether disulfidptosis exhibits heterogeneity in TNBC.
Methods:
Initial molecular subtyping was performed via K-means clustering. Subsequent subtype characterization included enrichment analysis, differential activity score (DA score) analysis, and in vitro drug sensitivity assays targeting disulfidptosis pathways. The prognostic model was derived through univariate Cox regression followed by least absolute shrinkage and selection operator (LASSO) regression of disulfidptosis-associated genes and metabolites. The prediction model was graphically displayed as a nomogram.
Results:
Through bioinformatics analysis of a TNBC multiomic dataset (n=465), we divided TNBCs into two disulfidptosis-related subtypes: cluster 1 and cluster 2. Compared with cluster 2, cluster 1 had an activated pentose phosphate pathway, an immunosuppressive microenvironment and a poor prognosis. We further confirmed that TNBC cell lines in cluster 1 were more sensitive to disulfidptosis induced by glucose deprivation or the inhibition of GLUT1. Moreover, the disulfidptosis-associated genes and metabolites-based predictive model demonstrated robust predictive performance.
Conclusions:
Taken together, our research demonstrated the heterogeneity of TNBC disulfidptosis and presented a promising treatment strategy for targeting disulfidptosis in TNBC.
Insights
Triple-negative breast cancer (TNBC) shows heterogeneity in disulfidptosis, a cell death pathway. This study identified two subtypes, revealing distinct metabolic and immune profiles, and developed a predictive model for targeted therapies.
Area of Science:
- Oncology
- Cell Biology
- Metabolic Pathways
Background:
- Triple-negative breast cancer (TNBC) is known for its heterogeneity and metabolic reprogramming.
- Disulfidptosis, a novel regulated cell death, is linked to cystine and cysteine metabolism.
- The heterogeneity of disulfidptosis in TNBC remains poorly understood.
Purpose of the Study:
- To investigate the heterogeneity of disulfidptosis in triple-negative breast cancer.
- To identify distinct subtypes of TNBC based on disulfidptosis-related features.
- To develop a predictive model for prognosis and treatment strategies.
Main Methods:
- K-means clustering for molecular subtyping of TNBC.
- Enrichment analysis and differential activity score (DA score) analysis for subtype characterization.
- In vitro drug sensitivity assays, univariate Cox regression, and LASSO regression for prognostic model development.
Main Results:
- Two disulfidptosis-related subtypes of TNBC were identified from a multiomic dataset (n=465).
- Cluster 1 exhibited an activated pentose phosphate pathway, an immunosuppressive microenvironment, and a poorer prognosis compared to cluster 2.
- Cluster 1 TNBC cell lines showed increased sensitivity to disulfidptosis induction via glucose deprivation or GLUT1 inhibition.
- A predictive model based on disulfidptosis-associated genes and metabolites demonstrated robust performance.
Conclusions:
- Disulfidptosis exhibits significant heterogeneity within triple-negative breast cancer.
- The identified subtypes offer insights into TNBC's metabolic and immune landscape.
- Targeting disulfidptosis presents a promising therapeutic strategy for TNBC.
