Growth differentiation factor 15 (GDF15) as a potential serum biomarker for malignant pleural mesothelioma

Introduction Malignant pleural mesothelioma (MPM) is a remarkably challenging and agressive cancer, often progressing rapidly with a poor prognosis Current first-line systemic treatments for unresectable MPM include dual immunotherapy (nivolumab + ipilimumab) or chemo-immunotherapy (pembrolizumab + pemetrexed + cisplatin). In selected patients, the chemotherapy doublet (cisplatin + pemetrexed) remains standard. The growth and differentiation factor 15 (GDF15) has recently emerged as a circulating biomarker linked to adverse outcomes in multiple cancers. It’s role in MPM is poorly understood. Materials and Methods Primary models: eight patient-derived MPM cell lines of different histological subtypes were established to support mechanistic and therapeutic studies. Cell labeling: Firefly luciferase-expressing derivatives of MM473, MM487, and MM432 cells were generated for in vivo tracking PDX generation: MM473 and MM487 cells formed orthotopic pleural xenografts in immunodeficient nude mice Molecular profiling: NA sequencing, gene expression microarray, and Gene Ontology (GO) analysis was conducted to identify genes potentially involved in MPM oncogenesis and cisplatin-response Data Validation: Public database and blood serum analysis were used to confirm GDF15 association with MPM prognosis Results Luciferase-tagged MM473 and MM487 successfully engrafted and recapitulated MPM growth in vivo. RNA sequencing and gene expression microarray analysis revealed GDF15 as a key up-regulated gene in pleural mesothelioma PDX cells compared to the non-cancerous mesothelium-derived epithelial cell line Met-5a and following cisplatin treatment. In vitro assays confirmed that GDF15 expression is enhanced by cisplatin treatment and is higher in PDX cells in respect to normal counterpart. In our MPM patient cohort, a substantial increase in the levels of the GDF15 molecule was identified in the peripheral blood samples, as compared to healthy individuals. From The Cancer Genome Atlas (TCGA) we observed that up-regulation of GDF15 associates with worse prognosis of MPM patients. Conclusion and Discussion We have established novel PDX models for the in vivo study of MPM development that recapitulate the growth characteristics and tumorigenic capability of human mesothelioma GDF15 likely plays a key role in promoting the proliferation and survival of MPM cells and is involved in cis-platin response, likely mediating chemoresistance to cisplatin treatment. Increased GDF15 levels in response to chemotherapy indicate its potential as a strategic target for combinatorial therapy approaches to overcome chemoresistance and immunotherapy resistance. GDF15 serum levels could be used as diagnostic/prognostic tools for MPM patients Our results suggest and support the need for further clinical investigation to correlate GDF15 serum levels with chemotherapy response in MPM patients and to assess the therapeutic potential of targeting GDF15—either alone or in combination with cisplatin or anti-PD-1 therapies—to overcome chemoresistance and immunotherapy resistance.