Abstract 964: Tumor cell plasticity promotes metastasis across heterogeneous tumors

Abstract

Abstract Metastasis, the growth of secondary tumors in distant organs, 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 that may influence metastasis formation. During the metastatic cascade, tumor cells adapt their phenotype to various microenvironments that are distinct from their original site resulting in heterogeneous metastatic cells that often are resistant to conventional treatment. The underlying mechanisms of why some tumor cells can give rise to metastases, whereas others cannot are remarkably poorly understood. We established patient-derived xenograft (PDX) models of breast cancer with different metastatic potential and preserved tumor heterogeneity. We analyzed the intrinsic cellular programs of individual tumor cells that influence the metastatic potential of breast cancers using different single-cell RNA-sequencing protocols (MULTI-Seq and Smart-Seq2). Using gene expression profiling of matched primary tumor and metastatic cells of 13 human breast cancers, we demonstrated that while human tumors showed profound inter-patient heterogeneity, they also shared signatures of differentially expressed genes between primary tumor and metastatic cells. Tumors with similar metastatic capabilities shared similar signatures, suggesting potential targets to directly treat metastasis. Additionally, we found that the plasticity of tumor cells is a common feature across tumors that is beneficial for the formation of metastasis. Tumors with higher levels of plastic tumor cells have a greater ability to form metastases. Moreover, we identified a subset of tumor cells expressing both markers of epithelial and mesenchymal characteristics, demonstrating in-vivo evidence for tumor epithelial-mesenchymal plasticity (EMP) in the metastatic cascade. The EMP is a continuum of states with epithelial and mesenchymal cell states as the two extremes of this continuum. The identified transition cells express distinct markers suggesting that these cells may represent a novel and overlooked cell type within the EMP continuum. Given the importance of tumor plasticity in the metastatic cascade, inhibiting the subset of tumor cells that are currently undergoing EMP may represent a novel treatment strategy for metastasis. Citation Format: Juliane Winkler, Weilun Tan, Angela O. Pisco, Andrei Goga, Spyros Darmanis, Zena Werb. Tumor cell plasticity promotes metastasis across heterogeneous tumors [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 964.