Abstract 351: Alterations in immune cell signatures during breast cancer metastasis at single cell resolution

Metastasis is the major cause of cancer-related deaths due to insufficient therapeutic effects of conventional treatment. Individual tumor cells exhibit heterogeneous features and growth potentials within the same tumor. This intra-tumor heterogeneity influences the ability of the tumor to form metastasis. The underlying mechanisms of why some tumor cells can give rise to metastases, whereas others cannot are remarkably poorly understood. Tumor cells acquire complex properties in order to invade into surrounding tissue, intravasate into the circulation, survive the journey to the distant site, where they extravasate into the new tissue and give rise to a secondary tumor. During this multistep process, tumor cells adapt their phenotype to various microenvironments that are distinct from their original site and are shaped by different immune and stromal cell populations. Metastatic tumor cells are heterogeneous and different from the primary tumor cells and may depend on the microenvironment at the distant site. Our study aims to better understand how the tumor heterogeneity influences the tumor-immune cell axis and how, in turn, immune cells support tumor cell plasticity and metastasis formation. We established patient-derived xenograft models of breast cancer with different metastatic potential and preserved tumor heterogeneity. We analyzed the gene expression of individual tumor and metastatic cells and their associated immune cell signature using a novel multiplexing approach for high-throughput single-cell RNA sequencing (MULTI-seq). In our study, we characterize the heterogeneity of different myeloid cells and their involvement in metastatic progression. Our data show that primary tumors from different individuals share a similar immune cell signature. However, metastasis-associated immune cells show distinct expression patterns related to the metastatic potential of the primary tumor and metastatic progression. In addition, prior to metastatic seeding, we identify an altered immune cell signature in the tissue distant from the primary breast tumor. Additionally, our data reveal that the plasticity of tumor cells is beneficial for the formation of metastasis. Tumors with higher levels of plastic tumor cells that undergo epithelial-mesenchymal-transition (EMT), have a greater ability to form metastasis. Our data indicate that subsets of immune cells of the myeloid lineage could promote this tumor plasticity and are enriched in tumors with higher metastatic potential. Thus, these innate immune cells provide a potential target for immune cell therapy, which may inhibit tumor cell plasticity and thereby the development of metastasis. Citation Format: Juliane Winkler, Weilun Tan, Christopher McGinnis, Zev Gartner, Spyros Darmanis, Zena Werb. Alterations in immune cell signatures during breast cancer metastasis at single cell resolution [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 351.