Journal of translational medicine · 2026
Single-cell transcriptomics reveals transcriptional reprogramming and microenvironmental remodeling in ectopic ACTH/CRH-secreting pheochromocytomas.
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Su Wan, Chen Shiwei, Liu Jinghua, Lian Penghu, Zhang Xuebin, Zhang Yushi, Han Wencong, Shen Qi, Zhang Di, Zhou Xiang, Xiao Yu, Ling Qing, Gao Ying, Lu Lin, Zhang Zheng
Аннотация
BACKGROUND: Ectopic ACTH- and/or CRH-secreting pheochromocytomas (ACTH+CRH+PCCs) are rare tumors that can mimic Cushing's syndrome and complicate the diagnosis and treatment clinically. However, the tumor-intrinsic and microenvironmental features of ACTH+CRH+ PCCs remains poorly understood.
METHODS: Fresh tumor specimens from three ACTH+CRH+ and three ACTH- CRH- PCCs were profiled by single-cell RNA sequencing. Developmental trajectories and transcriptional regulatory networks were analyzed to investigate tumor-intrinsic programs, while CellChat and NicheNet were used to characterize cell-cell communication and infer ligand-mediated microenvironmental remodeling. Findings were also validated using TCGA datasets and immunohistochemical staining.
RESULTS: ACTH+ CRH+ PCCs showed increased POMC and CRH expression and were enriched for a Schwann cell precursor (SCP)-like population positioned at an early pseudotime state. Regulatory network analysis further identified increased CEBPB activity in ACTH+ CRH+ tumor cells. Microenvironmental analysis revealed enrichment of SELE+ endothelial cells and CD8+ T cells in ACTH+ CRH+ PCCs. Cell-cell communication analysis showed more frequent interactions between ACTH+ CRH+ tumor cells and SELE+ endothelial cells, together with predicted ECM-associated interactions between SELE+ endothelial cells and T cells. In contrast, ACTH- CRH- PCCs exhibited stronger VEGFA-related angiogenic signaling, greater enrichment of stromal populations and MRC1+ M2-like macrophages, and more prominent LGALS9-CD45 signaling between macrophages and T cells.
CONCLUSIONS: Our study provides single-cell insights into the tumor-intrinsic and microenvironmental heterogeneity between ACTH+CRH+ PCCs and ACTH-CRH- PCCs, revealing distinct tumor cell states and subtype-specific vascular and immune landscapes.
METHODS: Fresh tumor specimens from three ACTH+CRH+ and three ACTH- CRH- PCCs were profiled by single-cell RNA sequencing. Developmental trajectories and transcriptional regulatory networks were analyzed to investigate tumor-intrinsic programs, while CellChat and NicheNet were used to characterize cell-cell communication and infer ligand-mediated microenvironmental remodeling. Findings were also validated using TCGA datasets and immunohistochemical staining.
RESULTS: ACTH+ CRH+ PCCs showed increased POMC and CRH expression and were enriched for a Schwann cell precursor (SCP)-like population positioned at an early pseudotime state. Regulatory network analysis further identified increased CEBPB activity in ACTH+ CRH+ tumor cells. Microenvironmental analysis revealed enrichment of SELE+ endothelial cells and CD8+ T cells in ACTH+ CRH+ PCCs. Cell-cell communication analysis showed more frequent interactions between ACTH+ CRH+ tumor cells and SELE+ endothelial cells, together with predicted ECM-associated interactions between SELE+ endothelial cells and T cells. In contrast, ACTH- CRH- PCCs exhibited stronger VEGFA-related angiogenic signaling, greater enrichment of stromal populations and MRC1+ M2-like macrophages, and more prominent LGALS9-CD45 signaling between macrophages and T cells.
CONCLUSIONS: Our study provides single-cell insights into the tumor-intrinsic and microenvironmental heterogeneity between ACTH+CRH+ PCCs and ACTH-CRH- PCCs, revealing distinct tumor cell states and subtype-specific vascular and immune landscapes.