Oncogenic driver and therapeutic target: Prolactin signalling axis in retroperitoneal sarcoma

BACKGROUND: Retroperitoneal sarcoma (RPS) is a type of malignant tumour arising from mesenchymal tissues within the retroperitoneal space. RPSs tend to develop covertly and are often undiscovered when they have already grown significantly and invaded surrounding tissues and organs. These malignancies demonstrate high recurrence rates, present surgical challenges and exhibit limited responsiveness to radiotherapy and chemotherapy. Serum-derived molecules are known to play critical roles in tumourigenesis and tumour progression. However, the serum molecular profile of RPS patients remains unclear. METHODS: We performed multi-omics analysis of serum samples from patients with retroperitoneal dedifferentiated liposarcoma. Prolactin concentrations were quantified using Enzyme-Linked Immunosorbent Assay (ELISA). RNA-seq facilitated the identification of candidate signalling pathways, while gene expression was validated through quantitative polymerase chain reaction, immunohistochemistry and western blot analyses. Molecular mechanisms underlying transcriptional regulation were investigated through Chromatin Immunoprecipitation-qPCR (ChIP-qPCR) and dual-luciferase reporter gene assays. RESULTS: Integrative multi-omics profiling identified significant perturbations in galactose metabolism coupled with marked elevation of prolactin (PRL) levels in Retroperitoneal Liposarcoma (RLPS) patients. Further screening of serum prolactin levels in 100 patients with retroperitoneal tumours revealed that 90% of the cases exhibited hyperprolactinaemia in our research cohort, encompassing both malignant sarcomas and benign tumours. Studies at the clinical sample, cellular and animal levels have found that abnormally elevated prolactin in the serum can originate from sarcoma tissues. Mechanistic investigations identified SRY-box transcription factor 4 (SOX4) as a previously unrecognised transcriptional regulator of PRL. Functionally, PRL not only enhanced liposarcoma cell and fibrosarcoma cell proliferation but also conferred resistance to MDM2 inhibitors. Signalling pathway analysis revealed that PRL activates the Janus Kinase-Signal Transducer and Activator of Transcription Pathway (JAK-STAT) signalling pathway and up-regulates c-MYC expression. CONCLUSIONS: This study indicates that PRL can serve as an oncogenic driver and therapeutic target. The identification of SOX4-PRL-c-MYC signalling axis provides actionable insights for developing novel therapeutic strategies against this malignancy. KEY POINTS: Retroperitoneal sarcoma cells can secrete prolactin into the bloodstream, inducing hyperprolactinaemia, which subsequently triggers metabolic reprogramming, such as glucose metabolism. SOX4 can function as a transcription factor that facilitates PRL transcription. PRL can activate the JAK-STAT signalling pathway by binding to PRLR on sarcoma cells, leading to the up-regulation of c-MYC.