Cancer stem cell transcriptomic signatures reveal patient-to-patient heterogeneity emphasizing the need for patient-specific ovarian cancer targets

Abstract

Background/Objectives In high-grade serous ovarian cancer (HGSOC), the abilities of tumor cells to resist cytotoxic treatment and relapse are largely driven by ovarian cancer stem cells (CSCs). CSCs are a population of cells within a tumor that maintain stem-like qualities and have the capacity to produce metastasis and drive drug resistance. Based on the complexity of CSC signaling and emerging evidence of differential isoform usage in development, we hypothesize that CSCs possess a patient-specific, heterogeneous landscape which exploits isoform diversity to sustain stemness, metastasis and drug resistance. Methods RNA-seq was generated from 3 patient-derived HGSOC (PD-HGSOC) to investigate stemness and differentiation status comparing standard culture and CSCs. The data was analyzed at both gene- and isoform-levels to identify patient-specific CSC features and define mechanisms of cancer-related stemness and plasticity. Results CSCs exhibited higher stemness characteristics and identified differentially expressed gene sets across PD-HGSOCs. We noted that each patient had a distinct subset of genes regulating stemness phenotypes which suggested multiple mechanisms of CSC development and maintenance. Additionally, a large proportion of gene-level expression changes were driven by the differential expression of a single predominant isoform. Importantly, our isoform-level analysis enabled the identification of differential isoform usage that would not be detected with gene level expression analysis. Conclusions CSC phenotypes such as chemoresistance, metastasis and self-renewal are conserved across patients, but arise from largely patient-specific gene and isoform programs. This CSC heterogeneity is reflective of the heterogeneity seen in patients and should be further evaluated in deriving precision-medicine approaches for HGSOC. Graphical Abstract Simple vs Patient-Specific CSC signatures. Created in BioRender. Perkins, R. (2026) https://BioRender.com/m8qwrmt Simple Summary Patients with advanced ovarian cancer have poor prognosis, no targeted treatment options and are often diagnosed at late stages due to rapid metastasis and vague symptoms. Cancer stem cells contribute to these poor patient outcomes via increased drug resistance, tumor relapse, and metastasis. Here we found that cancer stem cell phenotypes such as chemoresistance, metastasis and self-renewal are conserved across patients, but arise from largely patient-specific gene and isoform programs. This heterogeneity is reflective of the heterogeneity seen between patients and should be further evaluated in order to develop precision-medicine approaches for ovarian cancer. Our results provide foundational understanding of cancer stem cell plasticity, patient heterogeneity, and next generation drug design, increasing target specificity, and reducing adverse effects.