Endocrine Abstracts

Objectives: Attempts have been made to identify markers for aggressive disease in papillary microcarcinomas (PMCs), but genetic alterations identified in PMCs have failed to distinguish tumors with high-risk features. Thus, we aimed to identify candidate markers associated with lateral node metastasis (N1b) in patients with PMC through a transcriptomic analysis.

Methods: Bulk RNA sequencing was performed in 26 matched tumor and normal thyroid tissue samples (N0, n =14; and N1b, n =12). Analyses of principle component analysis (PCA), differentially expressed genes (DEGs), and functional enrichment were performed. To further explorer distinct tumor microenvironment (TME), EcoTyper, deconvolution tool, was applied.

Results: In PCA, PC2 axis divided tumor and normal thyroid tissue, but N1b tumor was not distinguishable from N0 tumor. We identified 631 DEGs between N1b and N0 PMCs (213 upregulated genes and 418 downregulated genes). The most significantly upregulated genes in N1b PMCs, including NECTIN4, NOX4, PDLIM4, COL11A1, MMP11, and POSTN, are related to tumorigenesis, adhesion, migration, and invasion. Functional enrichment analysis showed that DEGs were mainly enriched in the pulmonary fibrosis idiopathic signaling pathway, TME pathway, wound healing signaling pathway, and inhibition of matrix metalloproteases, and the activation of these pathways in N1b PMCs were predicted. Furthermore, deconvolution analyses revealed that N1b PMCs has a unique TME with abundant fibroblasts, and epithelial cells, and lymphocyte deficient, which are linked to higher risk. Consistently, fibroblast marker genes such as COL10A1, COL3A1, POSTN, MMP11, VCAN, TNFAIP6, LOXL2, FN1, and epithelial cell marker genes such as NOX4, MFAP2, TGFVBI, TNC, ICAM1, CXCL8, CSF2 were highly expressed in N1b PMCs compared to N0 PMC or normal thyroid tissue.

Conclusions: Transcriptomic analysis revealed that N1b PMC show the activation of TME pathway and a distinct TME with a high abundance of fibroblasts and epithelial cells compared to N0. Therefore, these TME state could be potential target for N1b PMC and lead to better stratification for high-risk PMC with lateral node metastasis.