High tumor cell platelet‐derived growth factor receptor beta expression is associated with shorter survival in malignant pleural epithelioid mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) has a rich stromal component containing mesenchymal fibroblasts. However, the properties and interplay of MPM tumor cells and their surrounding stromal fibroblasts are poorly characterized. Our objective was to spatially profile known mesenchymal markers in both tumor cells and associated fibroblasts and correlate their expression with patient survival. The primary study cohort consisted of 74 MPM patients, including 16 patients who survived at least 60 months. We analyzed location‐specific tissue expression of seven fibroblast markers in clinical samples using multiplexed fluorescence immunohistochemistry (mfIHC) and digital image analysis. Effect on survival was assessed using Cox regression analyses. The outcome measurement was all‐cause mortality. Univariate analysis revealed that high expression of secreted protein acidic and cysteine rich (SPARC) and fibroblast activation protein in stromal cells was associated with shorter survival. Importantly, high expression of platelet‐derived growth factor receptor beta (PDGFRB) in tumor cells, but not in stromal cells, was associated with shorter survival (hazard ratio [HR] = 1.02, p < 0.001). A multivariable survival analysis adjusted for clinical parameters and stromal mfIHC markers revealed that tumor cell PDGFRB and stromal SPARC remained independently associated with survival (HR = 1.01, 95% confidence interval [CI] = 1.00–1.03 and HR = 1.05, 95% CI = 1.00–1.11, respectively). The prognostic effect of PDGFRB was validated with an artificial intelligence‐based analysis method and further externally validated in another cohort of 117 MPM patients. In external validation, high tumor cell PDGFRB expression associated with shorter survival, especially in the epithelioid subtype. Our findings suggest PDGFRB and SPARC as potential markers for risk stratification and as targets for therapy.

SPARC Is a Novel Positive Immunohistochemical Marker of Epithelioid Mesothelioma to Differentiate It From Lung Adenocarcinoma and/or Squamous Cell Carcinoma

“…SPARC expression in tumor-associated stroma is instrumental in tumor survival and progression and serves as a prognostic factor 14,15,17 . In mesothelioma, SPARC is linked to epithelial-mesenchymal transition, 18 and both its expression in tumor stromal cells and blood SPARC levels correlate with prognosis 19,20 . In the current study, SPARC was found to be positive in mesothelioma cells and negative in lung cancer cells.…”

“…14,15,17 In mesothelioma, SPARC is linked to epithelial-mesenchymal transition, 18 and both its expression in tumor stromal cells and blood SPARC levels correlate with prognosis. 19,20 In the current study, SPARC was found to be positive in mesothelioma cells and negative in lung cancer cells. In the stromal context, focal-to-diffuse SPARC expression was observed in endothelial cells, fibroblasts, and macrophages.…”

A comprehensive study of alternative splicing in malignant pleural mesothelioma identifies potential therapeutic targets in a new cluster with poor survival

“…We found that the genes encoding PDGFRB, CSPG4, and COL1A2, which are highly expressed in MPM and correlate with MPM patient prognosis as reported earlier, were almost exclusively expressed in cluster 3 (Figure 3d). 28–30 All cluster 4 patients and 55% of cluster 3 patients belonged to the epithelioid pathology type, but showed significant differences in survival time. Therefore, we explored the differences between cluster 3 and cluster 4 only in epithelial‐type patients and found that they exhibited similar overall characteristics, which indicated that the difference in pathological type was not so important after classification according to alternative splicing clusters.…”

Prognostic Role of Tumor Immune Microenvironment in Pleural Epithelioid Mesothelioma

“…The clinical characteristics of the study population and specific details regarding the tissue microarrays have been described ( 20 ). We excluded patients with biphasic histology (n = 5).…”

“…The mfIHC staining, scanning, and digital cell–based image analysis methods have been previously described ( 20 , 21 ) and were utilized in the current study as described previously. Briefly, we designed and optimized five mfIHC panels (shown in Supplementary Table S1 ) including 21 antibodies targeting immune cell–specific antigens and analyzed the immune cell populations of interest ( Table 1 ) from the multichannel images using cell-based image analysis method.…”