Molecular classification and tumor microenvironment characteristics in pheochromocytomas

Area of Science:

• Endocrinology
• Oncology
• Genomics

Background:

• Pheochromocytomas (PCCs) are rare neuroendocrine tumors with incompletely understood cellular and immune characteristics.
• Single-cell RNA sequencing (scRNA-seq) offers a powerful tool to dissect tumor heterogeneity and microenvironment.

Purpose of the Study:

• To characterize the cellular molecular landscape and immune microenvironment of pheochromocytomas.
• To identify distinct molecular subtypes of PCCs and their potential therapeutic implications.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) was performed on 16 PCC tissues from sporadic and hereditary (VHL syndrome) patients.
• Immunohistochemical staining and multispectral immunofluorescence were used for validation.
• Trajectory analysis and cell-cell communication analysis were employed to understand tumor evolution and interactions.

Main Results:

• PCCs exhibit greater inter-individual than intra-tumoral heterogeneity.
• Two PCC subtypes were identified: metabolism-type (NDUFA4L2, COX4I2) and kinase-type (RET, PNMT).
• Metabolism-type PCCs show active metabolism and metastasis potential; kinase-type PCCs have reduced epinephrine synthesis and neuron-like phenotypes.
• Kinase-type PCCs downregulate HLA-I molecules, suggesting potential for kinase inhibitor and immunotherapy combinations.
• Metabolism-type PCCs show inflammation and annexin pathway activation; kinase-type PCCs show FGF signaling activation.

Conclusions:

• This study provides a single-cell transcriptomics-based classification of PCCs into metabolism-type and kinase-type.
• Kinase-type PCCs present a potential target for combined kinase inhibitor and immunotherapy.
• Metabolism-type PCCs, with their antigen presentation ability, may not be suitable for immunotherapy.