Abstract B083: Single-cell and spatial transcriptomic characterization of treatment resistance and immune dynamics in high-grade serous ovarian cancer
Authors: Imbach Kathleen J. , Naganathan Vikram , Bernabeu Arola Fortian , Grases Daniela , Bernat-Peguera Adrià , Bystrup Sara , Sibai Mustafa , Almeida Lorena Valdivieso , Romeo Margarita , Pardo Eduard Porta , Ginesta Jordi Barretina 
Published: March 2024

Abstract
High-grade serous ovarian carcinoma (HGSOC) is the most common epithelial ovarian cancer, characterized by genetic alterations imposing DNA repair deficiency and poor prognosis. Elucidating the molecular mechanisms of cancer development, treatment resistance and immune response in HGSOC is essential to improve clinical targeting and patient outcomes. In this pilot study, we leverage the capabilities of single-cell (sc) and spatial transcriptomics (ST) (10X Genomics platform) to characterize tumor samples from 5 HGSOC patients with variable chemotherapy (CT) response. We analyzed gene expression from the tumor landscape of 3 CT-sensitive patient samples taken at diagnosis, and 2 therapy-unresponsive patient samples taken after CT. In the scRNA-seq analysis, we observed that cancer cells from resistant post-CT samples exhibited upregulation of genes related to extracellular vesicles (EVs). A better understanding of the role of EVs in CT resistance may contribute to the development of novel therapeutic strategies by targeting EVs-mediated communication and cargo transfer. Additionally, our scRNA-seq analysis revealed that one CT-resistant, BRCAwt and homologous recombination proficient (HRP) sample exhibited a higher proportion of immune cells. Notably, cancer cluster data analysis showed intriguing differential expression of ligand/receptor genes, suggesting potential cell-cell communication mechanisms. At the spatial level, we similarly observed upregulation of vesicle-related genes in the malignant spots from CT-nonresponsive patients. Furthermore, the immune-enriched sample identified in the sc data also exhibited the highest contribution of immune-classified spatial spots, particularly demonstrating spatial colocalization of the LAMA5-BCAM ligand/receptor pair. These preliminary findings provide insights into the dysregulated pathways associated with chemotherapy resistance in the spatial context. Our study characterizes the gene expression patterns associated with CT treatment and immune response in ovarian cancer patients, showing the complex interplay between treatment resistance and immune dynamics. These findings emphasize the importance of identifying potential molecular targets, such as communication through EVs and immune signaling, to develop innovative therapeutic strategies to overcome treatment resistance and improve CT efficacy. Further investigation into the functional significance of these molecular targets may validate their potential as actionable targets for precision medicine approaches in ovarian cancer treatment.
Citation Format: Kathleen J. Imbach, Vikram Naganathan, Arola Fortian Bernabeu, Daniela Grases, Adrià Bernat-Peguera, Sara Bystrup, Mustafa Sibai, Lorena Valdivieso Almeida, Margarita Romeo, Eduard Porta Pardo, Jordi Barretina Ginesta. Single-cell and spatial transcriptomic characterization of treatment resistance and immune dynamics in high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B083.