Single-cell transcriptomics identify mechanical-memory–associated cell states in metastatic HR+ breast cancer

Sep 22, 2026

Mechanical memory has emerged as a key concept in tumor mechanobiology, yet a systematic definition of mechanical memory–related genes and their functional roles across cancers remains incomplete. This study curated mechanotransduction and mechanical memory pathways to build a 79-gene Mechanical Memory Signature (MMS) and assessed its expression and prognostic value across 32 cancer types using TCGA, then focused analyses on HR+ breast cancer single-cell RNA-seq.

LanguageEnglish

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Abstract

Background

Methods

Results

Conclusion

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Zhao et al. Breast Cancer Research (2026) 28:118 Breast Cancer Research [https://doi.org/10.1186/s13058-026-02280-1](https://doi.org/10.1186/s13058-026-02280-1) RESEARCH Open Access Single-cell transcriptomics identify mechanical-memory–associated cell states in metastatic HR+ breast cancer Xiwen Zhao1,2, Yuan Fan1,2, Jin Yang1,2* and Huan Gao1,2* Abstract 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. Keywords Mechanical memory, RELA, Extracellular matrix, Liver metastasis, ER+ breast cancer *Correspondence: Jin Yang [yangjin@mail.xjtu.edu](yangjin@mail.xjtu.edu)[ ](yangjin@mail.xjtu.edu)Huan Gao [huan20121213@163.com](huan20121213@163.com) 1Phase I Clinical Trial Research Center, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi, People’s Republic of China 2Department of Cancer Center, The First Affiliated Hospital of Xi’an Jiao tong University, Xi’an 710061, Shaanxi, People’s Republic of China © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the c

FAQs

What is mechanical memory in the context of tumor mechanobiology?

Mechanical memory refers to the ability of cancer cells to retain and integrate prior mechanical cues to influence future behaviors during tumor progression.

How was the Mechanical Memory Signature (MMS) constructed and validated?

Researchers curated literature-supported mechanotransduction and mechanical memory pathways to construct a 79-gene MMS, evaluated MMS patterns and prognostic relevance across cancers with TCGA datasets, and performed focused single-cell analyses in breast cancer. A 3D stiffness-tuned collagen model was used for experimental validation.

What role does RELA play in metastatic HR+ breast cancer?

Single-cell integration identified RELA as a central transcriptional node strongly correlated with MMS activity, linked to cytoskeletal remodeling and ECM-regulatory genes. Matrix stiffening increased RELA and MMP14 expression, and activating the RELA–RhoA axis amplified these effects even under softer matrix conditions.

Sep 22, 2026

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