Single-Cell Mapping of Malignant Signaling Networks Guides Drug Combinations

This study highlights the role of HIF-1 and other signaling pathways, including oxytocin, in breast cancer, suggesting they may inform future combination therapies.

Summary and findings

This study analyzed 15,753 malignant cells from untreated primary breast tumors to explore signaling pathways and their potential implications for combination therapy. The analysis identified recurrent pathways, including oxytocin signaling, and evaluated their significance in malignant-cell states. The study suggests that targeting these pathways may inform therapeutic strategies.

Abstract

Single-cell breast cancer atlases reveal malignant, immune, and stromal diversity; however, how the recurrent signaling pathways drive untreated malignant-cell states and could inform combination therapy remains unclear. Here, we analyzed 15,753 malignant cells from untreated primary breast tumors using a cell-resolved network framework. Individual transcriptomes were projected onto a protein–protein interaction network, partitioned into Leiden communities, and annotated by pathway enrichment. Pathway recurrence was evaluated against matched null models preserving community size, protein-network degree, and gene detection rate. Before null correction, recurrent pathways included PI3K/AKT, MAPK, JAK/STAT, and HIF-1 (hypoxia-inducible factor 1) signaling. After correction, HIF-1 emerged as the dominant recurrent signal across patients, indicating convergence of diverse upstream pathways on a shared hypoxia- and stress-adaptive malignant-cell program. The recurrent JAK/STAT, cAMP, glucagon, oxytocin, and thyroid hormone signaling suggest inflammatory, metabolic, and endocrine crosstalk. These findings support rational drug combinations targeting HIF-1 together with upstream PI3K/AKT/mTOR, MAPK, or JAK/STAT signaling.

Limitations

Not reported in abstract.

Elsewhere in the Oxytocin corpus