Abstract 4278: Targeting tumor pericyte-specific transcription factor heterodimer for anti-metastasis cancer therapy

Abstract Pericytes, mural cells that envelop capillaries, play a critical role in tumor metastasis. While current therapies targeting tumor pericytes (TPCs) effectively suppress tumor angiogenesis and growth, they paradoxically promote metastasis, highlighting the need for improved TPC-based strategies. In this study, we identified a TPC-specific transcription factor heterodimer, TCF21-TCF3, which is positively associated with hematogenous metastasis. TCF3 is essential for TCF21-mediated collagen hydroxylation, facilitating extracellular matrix deposition and accelerating tumor metastasis. Using hydrogen-deuterium exchange mass spectrometry (HDX-MS), transverse relaxation-optimized spectroscopy (TROSY) NMR, and mutational analysis, we characterized the interacting residues of the TCF21-TCF3 heterodimer. A peptide designed to disrupt the TCF21-TCF3 interaction inhibited the formation of the heterodimer, downregulated TCF21/TCF3-dependent gene expression, and suppressed malignant behaviors, effectively reducing metastasis. This study proposes that targeting TPC-specific transcription factor heterodimers offers a promising therapeutic approach to combat tumor metastasis. Citation Format: Junqiu Zhang, Wenqian Yin, Minfeng Chen, Yi Xue, Wencai Ye, Dongmei Zhang. Targeting tumor pericyte-specific transcription factor heterodimer for anti-metastasis cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4278.