SAA1 Promotes Pro-inflammatory Macrophage-mediated Bone Invasion in Silent Corticotroph Adenomas.

Abstract

Silent corticotroph adenomas (SCAs) represent a high-risk subtype of pituitary neuroendocrine tumors, characterized by significant clinical heterogeneity and unclear pathogenesis. The multimicrocystic sign is a typical radiological feature of SCAs; however, its biological significance remains unclear. Here, we show that the characteristics of cystic changes reflect tumor evolutionary stages and are correlated with invasiveness and proliferative activity. We performed multi-omics analysis to identify key molecular drivers and revealed that serum amyloid A1 (SAA1) is highly expressed in microcystic tumors corresponding to the bone invasion stage. Our results demonstrate that SAA1 activates the TLR4/NF-κB pathway in macrophages, promoting pro-inflammatory macrophage polarization, TNF-α and CSF-1 secretion, and osteoclast differentiation. Spatial transcriptomics confirmed a significant correlation between the proportion of SAA1+ tumor cells and that of TNF-α+ macrophages. Serum amyloid A (SAA) levels in serum exhibited strong diagnostic value for SCAs. These findings highlight the potential clinical and biological significance of cyst size in SCAs and uncover a novel mechanism by which SAA1 drives tumor bone invasiveness through macrophage-mediated osteoclast differentiation. Our findings highlight that serum SAA levels may serve as a promising biomarker for the preoperative identification of SCAs, advancing our understanding of SCA heterogeneity.