Cancer cells can exploit normally dormant embryonic stem cell pathways to promote cancer progression. Studying embryonic signaling pathways in aggressive cancers has led to the discovery of the re-expression of the embryonic protein Nodal. It maintains pluripotency and cell plasticity of human embryonic stem cells. In many cancers Nodal signalling promotes tumor growth and metastasis. The objective of this study is to investigate the role of Nodal as a potential biomarker of ovarian cancer (OC) progression and resistance to chemotherapy.
We applied bioinformatics approach and RNA sequencing to investigate the impact of Nodal on biological processes in OC cells and disease outcome in OC patients (TCGA data). In vitro assays designed to assess cancer stem cell phenotypes and chemoresistance in OC cells wherein Nodal was overexpressed, or knocked out with CRISP/Cas9 genome editing were conducted. We performed IHC staining of Nodal in tissue microarrays of high-grade serous OCs (HGSOC) to evaluate prognostic significance of Nodal. HGSOC samples were obtained from Ovarian Cancer in Alberta and British Columbia study (OVAL-BC) cohort of OC patients (563 HGSOC samples).
RNA seq data showed that Nodal induces transcriptional reprogramming in OC cells via altering immune response, metabolism and drug resistance gene expression. In vitro, we showed that Nodal is a stress response gene which expression and protein increased in OC cells after treatment with cisplatin/carboplatin and retained for 96h after drug withdrawal. OC cells overexpressing Nodal characterized by increased resistance to cytostatic drugs, tumorigenicity and cell plasticity (partial EMT and stem cell-like phenotype). Analysis of TCGA microarray data and IHC staining of tissue microarrays of HGSOCs determined that Nodal predicts poor overall and progression-free survival in HGSOC patients.
Nodal predicts poor survival in HGSOC patients and likely drives tumorigenic potential and resistance to platinum in OC cells by promoting cancer stem cell plasticity and upregulating target genes involved in immune response, drug resistance and metabolism, and may hold promise as a therapeutic target to prevent disease recurrence following chemotherapy.
Clinical trial identification
Legal entity responsible for the study
All authors have declared no conflicts of interest.