Background and objective

Over the past two decades, the occurrence of thyroid cancer has shown a consistent upward trend. While the majority of thyroid cancers tend to be relatively slow-growing, it is noteworthy that distant metastases occur in 1-4% of cases, often leading to fatal outcomes. Among differentiated thyroid cancers, follicular thyroid carcinoma (FTC) stands out as having a higher risk of developing distant metastases, accounting for approximately 25% of such cases. Despite this, the underlying mechanism behind FTC distant metastases remains elusive.

Materials and Methods

To describe the molecular changes, we collected 66 formalin-fixed paraffin-embedded (FFPE) slides obtained from 66 FTC patients with (N=25) and without (N=41) distant metastasis. The distant metastasis group can be further divided into three subgroups: 8 cases of bone metastasis, 11 cases of lung metastasis, and 6 cases of combined lung and bone metastasis. The samples were prepared through a pressure cycling technology-assisted pipeline, proteomic data were acquired by PulseDIA mode on timsTOF Pro and searched by DIA-NN (v1.8.1) against a thyroid-specific spectral library.

Preliminary results

In this dataset, we quantified 11,044 proteins and identified 135 deferentially expressed proteins (DEPs) between the patients with and without distant metastases. These two groups of samples can be partially differentiated by uniform manifold approximation and projection analysis using the DEPs. Moreover, the pathway and function analysis revealed that extracellular matrix organization, cell matrix adhesion and collagen fibril organization were significantly dysregulated in the thyroid cancer metastasis. Based on the DEPs, we established an Xgboost model for the protein feature selection and stratification. Our model achieved an AUC of 0.848 under 10 features.

Next, we delve deep into the intricate mechanisms underlying tumor metastases across various organs. Through differential protein screening and cluster analysis, we uncovered that lung metastases are intimately linked to ECM perturbations, bone metastases are associated with immune dysregulation, and combined metastases exhibit complex interactions involving both metabolic alterations and immune dysregulation.

Conclusion

This study will provide clues for the understanding of the molecular mechanisms of distant metastasis in FTC, and provide a theoretical basis for improving clinical patient management and potential therapeutic options.