Introduction

Beyond near ubiquitous TP53 mutations, high-grade serous ovarian cancer (HGSC) is associated with the accumulation of genetic aberrations with few recurrent features. We have questioned whether, despite the complex genetics, developmental regulatory mechanisms constrain malignant phenotypes, producing recurrent patterns of intratumoural heterogeneity. These states may distinctly contribute to tumour progression and treatment response, and therapeutic strategies to polarize malignant cell identity may improve patient outcomes.

Results

We have analyzed scRNA-seq data from >100 HGSC tumours and found that malignant cells within individual tumours adopt four recurrent phenotypes: two secretory phenotypes (SecA, PAX8+, LGR5+; SecB, PAX8+, KRT7/17-high) and one ciliated (Cil; FOXJ1+, AGR3+), each sharing features with distinct populations found in the healthy fallopian tube epithelium; and a dedifferentiated (PAX8-) population expressing mesenchymal features (Mes, FN1+, VIM+, DES+), sharing cytokeratin (KRT8+, KRT19+) expression patterns with other malignant cells and similar copy number alterations based on computational inference. These states often co-occur within treatment-naive adnexal tumours, but SecB and Mes phenotypes are strongly enriched in both chemotherapy-treated tumours (interval debulking) and ascites. 

Conclusions

Current therapeutic approaches for HGSC often fail to recurrent disease and acquired resistance. These approaches do not account for intratumoural heterogeneity and adaptive mechanisms employed by malignant cells. By studying the phenotypic constraints of malignant cells, we aim to better understand how they evolve under the selective pressures within the tumour microenvironment. This information can ultimately inform rational treatment regimens that improved patient outcomes.