Work

Single‐nucleus RNA sequencing reveals the distinct heterogeneity of primary pulmonary sarcomas (PPS) and pulmonary sarcomatoid carcinoma (PSC)

Year: 2025

Type: article

Abstract: BACKGROUND: Primary pulmonary sarcomas (PPS) and pulmonary sarcomatoid carcinoma (PSC) are rare and aggressive diseases that pose significant diagnostic challenges, requiring extensive sampling and comprehensive evaluation. To date, the single-cell characteristics and distinctions between these two conditions have not been thoroughly investigated. METHODS: In this study, we employed single-nucleus RNA sequencing (snRNA-seq) to characterise the cellular heterogeneity of PSC and PPS. Our analysis included 20 PSC samples, seven PPS samples and two non-malignant control samples obtained from adjacent normal tissue. RESULTS: Our results revealed that the majority of cells in PSC were of epithelial origin, while fibroblasts predominated in PPS. Specifically, AT2 cells, a major source of epithelial cells in PSC, underwent malignant transformation primarily through epithelial-mesenchymal transition, suggesting AT2 cells may serve as the origin of PSC. High Mobility Group AT-Hook 2 (HMGA2) expression was elevated in malignant AT2 cells of PSC and correlated with an unfavourable prognosis. Moreover, MET-mutated patients have a significantly higher expression level of HMGA2 (p < .001). In PPS, fibroblasts constituted the majority, only lipofibroblasts exhibited malignant features. A direct comparison between PSC and PPS lipofibroblasts revealed largely similar expression profiles, with the exception of an enrichment in DNA repair pathways specifically observed in PPS lipofibroblasts. CONCLUSION: These findings provide novel insights of PSC and PPS at the single-cell level. KEY POINTS: Distinct Cellular Origins: PSC arises primarily from epithelial (AT2) cells via EMT, whereas PPS is predominantly fibroblast-derived. Prognostic Driver HMGA2: Elevated HMGA2 in malignant AT2 cells correlates with poor prognosis and is significantly higher in MET-mutated PSC. Pathway Divergence in Malignant Cells: Malignant lipofibroblasts in PPS share a similar profile with PSC but uniquely enrich DNA repair pathways.

Source: Clinical and Translational Medicine

DOI: 10.1002/ctm2.70566