ABSTRACT
High-grade serous ovarian carcinoma (HGSOC) is genetically unstable and characterised by the presence of subclones with distinct genotypes. Intratumoural heterogeneity is linked to recurrence, chemotherapy resistance, and poor prognosis. Here, we use spatial transcriptomics to identify HGSOC subclones and study their association with infiltrating cell populations. Visium spatial transcriptomics reveals multiple tumour subclones with different copy number alterations present within individual tumour sections. These subclones differentially express various ligands and receptors and are predicted to differentially associate with different stromal and immune cell populations. In one sample, CosMx single molecule imaging reveals subclones differentially associating with immune cell populations, fibroblasts, and endothelial cells. Cell-to-cell communication analysis identifies subclone-specific signalling to stromal and immune cells and multiple subclone-specific autocrine loops. Our study highlights the high degree of subclonal heterogeneity in HGSOC and suggests that subclone-specific ligand and receptor expression patterns likely modulate how HGSOC cells interact with their local microenvironment.
Subject(s)
Ovarian Neoplasms , Tumor Microenvironment , Humans , Female , Tumor Microenvironment/genetics , Endothelial Cells/metabolism , Ovarian Neoplasms/pathology , Gene Expression Profiling , DNA Copy Number VariationsABSTRACT
Triple negative breast cancer (TNBC) is a heterogeneous subset of breast cancer characterized by its lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), which altogether prevents TNBC from being treated effectively. For many years, the treatment paradigms and overall survival of patients with TNBC have remained largely stagnant. Recent attempts to convert cold tumors to hot tumors by promoting antigen presentation have shown increased T cell infiltration and significantly induced immune responses for tumor killing. Inspired by this concept, the expression of specific targetable antigens on TNBC cells may further benefit relevant targeted drug delivery. In this study, we successfully conferred sufficient HER2 on the surface of TNBC MDA-MB-231 cells via simple EV-plasma membrane fusion with HER2+ extracellular vesicles (EV) derived from HER2 overexpressing BT-474 cells. Subsequently, anti-HER2 antibody conjugated paclitaxel-loaded liposomes were used for HER2-targeted drug delivery. Our findings demonstrated this HER2 grafting, in conjunction with targeted drug delivery, can improve the treatment efficacy in vitro and in vivo. This novel approach represents a facile method of altering cell membrane antigen presentation via convenient EVs uptake and may pave the way for the burgeoning wave of targeted therapy and/or immunotherapy.
