2. Academic Validation
  3. Local soft niches in mechanically heterogeneous primary tumors promote brain metastasis via mechanotransduction-mediated HDAC3 activity

Local soft niches in mechanically heterogeneous primary tumors promote brain metastasis via mechanotransduction-mediated HDAC3 activity

  • Sci Adv. 2025 Feb 28;11(9):eadq2881. doi: 10.1126/sciadv.adq2881.
Kai Tang 1 2 3,  Yufan Zheng 1 2 3,  Guanshuo Hu 1 2 3,  Ying Xin 1 2 3,  Keming Li 1 2 3,  Cunyu Zhang 1 2 3,  Xi Chen 1 2 3,  Bai Zhang 1 2 3,  Xueyi Li 1 2 3,  Bing Hu 1 2 3,  Qiong Jia 4,  Yong-Ping Zheng 2 3,  Mo Yang 3,  Youhua Tan 1 2 3
Affiliations

Affiliations

  • 1 The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, China.
  • 2 Research Institute of Smart Ageing, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China.
  • 3 Department of Biomedical Engineering, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China.
  • 4 Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China, 210006.
PMID: 40009679 DOI: 10.1126/sciadv.adq2881
Abstract

Tumor cells with organ-specific metastasis traits arise in primary lesions with substantial variations of local niche mechanics owing to intratumoral heterogeneity. However, the roles of mechanically heterogeneous primary tumor microenvironment in metastatic organotropism remain an enigma. This study reports that persistent priming in soft but not stiff niches that mimic primary tumor mechanical heterogeneity induces transcriptional reprogramming reminiscent of neuron and promotes the acquisition of brain metastatic potential. Soft-primed cells generate brain metastases in vivo through enhanced transendothelial migration across blood-brain barrier and brain colonization, which is further supported by the findings that tumor cells residing in local soft niches of primary xenografts exhibit brain metastatic tropism. Mechanistically, soft niches suppress cytoskeleton-nucleus-mediated mechanotransduction, which promotes histone deacetylase 3 activity. Inhibiting histone deacetylase 3 abolishes niche softness-induced brain metastatic ability. Collectively, this study uncovers a previously unappreciated role of local niche softness within primary tumors in brain metastasis, highlighting the significance of primary tumor mechanical heterogeneity in metastatic organotropism.

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