Breast cancer research : BCR · 2026
Single-cell transcriptomics identify mechanical-memory-associated cell states in metastatic HR+ breast cancer.
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Zhao Xiwen, Fan Yuan, Yang Jin, Gao Huan
Аннотация
BACKGROUND: Mechanical memory has recently emerged as an important concept in tumor mechanobiology, reflecting the ability of cancer cells to retain and integrate past mechanical cues to guide future behaviors. However, a systematic definition of mechanical memory-related genes and their functional implications across cancers remains lacking.
METHODS: We curated literature-supported mechanotransduction and mechanical memory pathways to construct a 79-gene Mechanical Memory Signature (MMS). MMS expression patterns and prognostic relevance were evaluated across 32 cancer types using TCGA datasets, followed by focused analyses in breast cancer. Single-cell RNA sequencing datasets containing primary and liver metastatic hormone receptor-positive (HR+) breast cancer cells were used to assess MMS activity at single-cell resolution. Pseudotime and transcriptional regulatory analyses were performed to define MMS-associated cellular states. A three-dimensional stiffness-tuned collagen mechanical memory model was employed for experimental validation.
RESULTS: MMS expression was broadly elevated in aggressive tumors and predicted unfavorable survival outcomes, with the strongest association observed in breast cancer. Single-cell integration revealed MMS-high tumor cell clusters exhibiting a progressive rise in MMS activity along pseudotime, suggesting acquisition and persistence of mechanical memory during metastatic evolution. Within these clusters, RELA was identified as a central transcriptional node strongly correlated with MMS activity and linked to cytoskeletal remodeling and ECM-regulatory genes, including PFN1, CFL1, RHOA, TIMP1, and MMP14. In 3D collagen cultures, matrix stiffening markedly increased RELA and MMP14 expression, while pharmacological activation of the RELA-RhoA axis further amplified this effect even under soft matrix conditions.
CONCLUSION: Our study revealed RELA as a key mediator of mechanical memory-driven metastatic behavior in ER+ breast cancer, providing a mechanistic framework and actionable targets for understanding and potentially disrupting mechanically informed tumor progression.
METHODS: We curated literature-supported mechanotransduction and mechanical memory pathways to construct a 79-gene Mechanical Memory Signature (MMS). MMS expression patterns and prognostic relevance were evaluated across 32 cancer types using TCGA datasets, followed by focused analyses in breast cancer. Single-cell RNA sequencing datasets containing primary and liver metastatic hormone receptor-positive (HR+) breast cancer cells were used to assess MMS activity at single-cell resolution. Pseudotime and transcriptional regulatory analyses were performed to define MMS-associated cellular states. A three-dimensional stiffness-tuned collagen mechanical memory model was employed for experimental validation.
RESULTS: MMS expression was broadly elevated in aggressive tumors and predicted unfavorable survival outcomes, with the strongest association observed in breast cancer. Single-cell integration revealed MMS-high tumor cell clusters exhibiting a progressive rise in MMS activity along pseudotime, suggesting acquisition and persistence of mechanical memory during metastatic evolution. Within these clusters, RELA was identified as a central transcriptional node strongly correlated with MMS activity and linked to cytoskeletal remodeling and ECM-regulatory genes, including PFN1, CFL1, RHOA, TIMP1, and MMP14. In 3D collagen cultures, matrix stiffening markedly increased RELA and MMP14 expression, while pharmacological activation of the RELA-RhoA axis further amplified this effect even under soft matrix conditions.
CONCLUSION: Our study revealed RELA as a key mediator of mechanical memory-driven metastatic behavior in ER+ breast cancer, providing a mechanistic framework and actionable targets for understanding and potentially disrupting mechanically informed tumor progression.