Transcriptomic Association of COL3A1+ Fibroblasts With Mechanical Pain-Related Gene Signatures in Triple-Negative Breast Cancer.

BACKGROUND

Epidemiological data show that approximately 80% of cancer patients experience pain of varying degrees throughout the course of their disease, with nearly one-third experiencing severe pain, significantly impacting their quality of life and the effectiveness of antitumor treatment. Triple-negative (TN) breast cancer tissues typically exhibit increased stromal stiffness and abnormally elevated mechanical stress; these biomechanical alterations may amplify pain signals by activating mechanosensitive channels. Utilizing single-cell RNA sequencing analysis, this study aims to elucidate the potential biological links between fibroblast mechanotransduction and cancer-associated pain, thereby providing a theoretical basis for clinical diagnosis and treatment.

METHODS

Dimensionality reduction and unsupervised clustering were used to identify cell types in TN breast cancer single-cell RNA sequencing data. To assess the association between pain and mechanical stimulation, we constructed a set of gene signatures associated with mechanical stimulation and pain and calculated scores using the Area Under the Curve Cell (AUCell). CellChat and SCENIC were used to reveal the communication networks and transcription factor regulatory mechanisms of fibroblast subtypes.

RESULTS

COL3A1+ fibroblasts derived from TN breast cancer are highly involved in biological processes such as extracellular matrix remodeling, collagen fiber formation, and mechanotransduction. To assess the association between pain and mechanical stimulation, we constructed a gene signature set related to mechanical stimuli and pain and calculated corresponding scores using the AUCell tool. Cell communication studies showed that COL3A1+ fibroblasts interact extensively with epithelial cells and other cells through laminin and collagen signaling pathways, potentially leading to mechanotransduction remodeling of the TN breast cancer microenvironment.

CONCLUSION

COL3A1+ fibroblasts demonstrate enhanced transcriptional profiles pertinent to collagen deposition and cytoskeletal reorganization, which are correlated with mechanotransduction signaling and may be connected with mechanical sensitivity in cancer-related pain. This study systematically characterizes the potential relationship between fibroblast-associated mechanotransduction characteristics and pain-related gene signatures at the single-cell level in TN breast cancer. These findings offer hypothesis-generating insights into the molecular landscape of tumor-associated pain, although additional experimental and clinical validation is necessary.