Local Soft Niches in Mechanically Heterogeneous Primary Tumors Promote Brain Metastasis Via Mechanotransduction-mediated HDAC3 Activity

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2025 Feb 26

PMID 40009679

Authors

Kai Tang

Yufan Zheng

Guanshuo Hu

Ying Xin

Keming Li

Cunyu Zhang

Xi Chen

Bai Zhang

Xueyi Li

Bing Hu

Qiong Jia

Yong-Ping Zheng

Mo Yang

Youhua Tan

Affiliations

Soon will be listed here.

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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