Abstract Background: Metastasis-associated protein-1 (MTA1) is a chromatin regulator that drives epithelial-to-mesenchymal transition (EMT), invasion, and metastatic competence in aggressive cancers including triple-negative breast cancer (TNBC). While tumor-cell MTA1 roles are well documented, its stromal contribution within mesenchymal stem cells (MSCs)—key regulators of the tumor microenvironment—remains largely unexplored. We investigated whether genetic silencing of MTA1 in human MSCs reprograms the tumor microenvironment to restrain TNBC progression and distant metastasis. Methods: Human MSCs were stably transfected with MTA1-shRNA or scrambled control. Knockdown was confirmed by qPCR and immunoblotting. Functional assays included MMP-2 activity, osteogenic differentiation markers (RUNX2, DMP1), endothelial tube formation, and TNBC (MDA-MB-231) 3D spheroid migration, invasion, and EMT profiling. Orthotopic MSC-TNBC spheroid co-implants were established in NSG mice (n=5-8/group) to assess tumor growth, lung and brain metastases, and histologic EMT and proliferation markers. Metastasis was quantified using macrometastatic scoring, H80% and suppressed MMP-2 activity by 66%. Osteogenic differentiation was markedly reduced (RUNX2 and DMP1 each ↓60%), and angiogenic tube formation decreased by 61%. In 3D co-culture, MTA1-KD MSCs reduced TNBC migration (↓54%) and invasion (↓57%) and induced EMT reversal with increased E-cadherin and decreased Vimentin and Snail. In vivo, MTA1-KD MSCs significantly inhibited tumor growth (∼48% reduction at day 56). Lung and brain metastases were profoundly reduced, with a 93% decrease in lung micrometastatic foci validated by macrometastasis scoring, H Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4846.
Mutahar et al. (Fri,) studied this question.