Single-cell RNA sequencing captures patient-level heterogeneity and associated molecular phenotypes in breast cancer pleural effusions

Whitfield, HJ; Berthelet, J; Mangiola, S; Bell, C; Anderson, RL; Pal, B; Yeo, B; Papenfuss, AT; Merino, D; Davis, MJ

Author(s): Whitfield, HJ; Berthelet, J; Mangiola, S; Bell, C; Anderson, RL; Pal, B; Yeo, B; Papenfuss, AT; Merino, D; Davis, MJ;
Details: Publication Year 2023-09,Volume 13,Issue #9,Page e1356
Journal Title: Clinical & Translational Immunology
Publication Type: epub ahead of print
Abstract: BACKGROUND: Malignant pleural effusions (MPEs) are a common complication of advanced cancers, particularly those adjacent to the pleura, such as lung and breast cancer. The pathophysiology of MPE formation remains poorly understood, and although MPEs are routinely used for the diagnosis of breast cancer patients, their composition and biology are poorly understood. It is difficult to distinguish invading malignant cells from resident mesothelial cells and to identify the directionality of interactions between these populations in the pleura. There is a need to characterize the phenotypic diversity of breast cancer cell populations in the pleural microenvironment, and investigate how this varies across patients. METHODS: Here, we used single-cell RNA-sequencing to study the heterogeneity of 10 MPEs from seven metastatic breast cancer patients, including three Miltenyi-enriched samples using a negative selection approach. This dataset of almost 65 000 cells was analysed using integrative approaches to compare heterogeneous cell populations and phenotypes. RESULTS: We identified substantial inter-patient heterogeneity in the composition of cell types (including malignant, mesothelial and immune cell populations), in expression of subtype-specific gene signatures and in copy number aberration patterns, that captured variability across breast cancer cell populations. Within individual MPEs, we distinguished mesothelial cell populations from malignant cells using key markers, the presence of breast cancer subtype expression patterns and copy number aberration patterns. We also identified pleural mesothelial cells expressing a cancer-associated fibroblast-like transcriptomic program that may support cancer growth. CONCLUSIONS: Our dataset presents the first unbiased assessment of breast cancer-associated MPEs at a single cell resolution, providing the community with a valuable resource for the study of MPEs. Our work highlights the molecular and cellular diversity captured in MPEs and motivates the potential use of these clinically relevant biopsies in the development of targeted therapeutics for patients with advanced breast cancer.
Publisher: Wiley
Keywords: Humans; Female; *Breast Neoplasms/genetics; *Pleural Effusion; Biopsy; Phenotype; Sequence Analysis, RNA; Tumor Microenvironment/genetics
Research Division(s): Bioinformatics
PubMed ID: 37691350
Publisher's Version: https://doi.org/10.1002/ctm2.1356
Open Access at Publisher's Site: https://doi.org/10.1002/ctm2.1356
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-09-21 11:41:21

Last Modified: 2023-09-21 12:09:28