Abstract SY31-01: Tissue resident macrophages and a mesenchymal-like program control early disseminated cancer cell dormancy
Authors: Aguirre-Ghiso Julio A. 
Published: June 2022

Tissue resident macrophages and a mesenchymal-like program control early disseminated cancer cell dormancy. Julio A. Aguirre-GhisoDepartment of Cell Biology, Department of Medicine-Oncology, Cancer Dormancy and Tumor Microenvironment Institute, Albert Einstein Cancer Center, Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Increasing evidence shows that cancer cells can disseminate from early-evolved primary lesions much earlier than the classical metastasis models predicted. The current paradigm supports that the tissue microenvironment where disseminated cancer cells (DCCs) lodge is a critical determinant of the timing of metastasis. However, how tissue-resident myeloid cells control this process is largely unclear. The lung tissue contains a resident population of alveolar macrophages (AMs), whose function in metastatic dormancy and growth is largely unexplored. Here, we used various transgenic mouse models, human sample analysis and single cell RNA-sequencing to reveal DCC heterogeneity and plasticity in the lung across disease evolution. We found a previously unrecognized role of mesenchymal- and pluripotency-like (M-like) programs driven by the transcription factor ZFP281 in coordinating early cancer cell spread and a long-lived dormancy program in early DCCs. The gene profiles revealed molecules that would allow early DCCs to crosstalk with AMs. Using a 3D Matrigel assay, we found that AMs are responsible for inducing an M-like phenotype in cancer cells (of both early and late evolved cancer cells) and exclusively suppressed growth of early lesion (EL) HER2+ cancer cells. The conditioned media (CM) from AMs was also found to induce an M-like phenotype and growth arrest of EL cells. RNA-sequencing profiling of pure EL cells and AMs that had been co-cultured revealed a reciprocal influence of the two cell types: increased ECM organization and induction of invasiveness in EL cells, as well as changes in inflammatory response and immune programs in AMs. Prediction of ligand-receptor interactions using the NATMI tool allowed for identification of signaling axis that would allow AMs to induce an M-like and growth program in EL cells. To test whether indeed AMs are inducing an M-like and growth arrest phenotype in early DCCs in lungs, we depleted AMs in mice bearing early MMTV-HER2 or late evolved E0771 breast cancer cells in lungs via intranasal instillation of clodronate liposomes or via the use of a AM=specific CD169-DTR targeting system. Following AM depletion, dormant DCCs began to proliferate and formed clusters and overt metastases. Our results support that tissue resident macrophages play a key role in limiting metastatic expansion of breast cancer cells via the induction of a DCC mesenchymal-like dormancy program.

Citation Format: Julio A. Aguirre-Ghiso. Tissue resident macrophages and a mesenchymal-like program control early disseminated cancer cell dormancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY31-01.