Abstract 1504: Tumor microenvironment-mediated regulation of early dissemination and colonization in breast cancer via BAZ2A-containing remodeling complexes

Abstract

Abstract The molecular mechanisms governing invasion, dissemination, extravasation, and early metastatic colonization remain incompletely understood. In the BALB-neuT mouse model, we found that most metastases originate from disseminated cancer cells (DCCs) that left the primary site early in tumorigenesis, i.e. when lesions are still small. Consequently, we investigated whether cellular density and the tumor microenvironment synergize to generate the plasticity needed during metastasis. RNA-sequencing analyses of murine breast cancer cells in low cellular density (LD) and high cellular density (HD) conditions revealed distinct profiles of differentially expressed genes. Notably, we identified the enrichment of ribosomal RNA (rRNA) and chromatin remodeling pathways in LD conditions. Interestingly, once these cells were treated with Wnt4 and Rankl, factors secreted by the tumor microenvironment, the expression profile of genes involved in proliferation, migration and stemness as well as epigenetic-related factors changed drastically. Specifically, cells in LD conditions treated with Wnt4 and Rankl displayed induced migration and stemness phenotypes, whereas under HD conditions, these signals induced proliferation. Among the chromatin-remodeling pathways, we found that BAZ2A along with the rRNA regulating network were primarily upregulated in migratory cancer cells. Immunostaining of primary and metastatic lesions in murine and human breast cancer samples showed an upregulation of BAZ2A in early/microlesions compared to more advanced and proliferative macroscopic lesions. Taken together, these results indicate that cell density, tumor microenvironmental factors and BAZ2A-containing chromatin regulating complexes play pivotal roles in regulating cancer cell plasticity in breast cancer. Additional sequencing and functional analyses will be performed to dissect the specific components of this mechanism and evaluate their impact on the in vivo colonization of breast cancer models. Citation Format: Miriam Kokal-Ribaudo, Nora Jahnen, Saba Sameri, Fulvia Ferrazzi, Renato Liguori, Christoph A. Klein, Gernot Längst, Hedayatollah Hosseini. Tumor microenvironment-mediated regulation of early dissemination and colonization in breast cancer via BAZ2A-containing remodeling complexes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1504.