SPP1+ macrophage-induced CD74+ tumor cells promote adrenocortical carcinoma tumor thrombus via the SPP1/CD44/JAK/STAT signaling

Abstract

Abstract Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine malignancy with limited treatment options and poor prognosis. Venous tumor thrombus (VTT) is a common complication associated with ACC progression, yet the cellular and molecular mechanisms driving VTT formation remain largely unknown. We performed integrated single-cell RNA sequencing and spatial transcriptomics on paired samples of primary tumor, VTT tail, and VTT head obtained from one ACC patient, followed by in vitro and in vivo functional validation. Our results identified a distinct CD74+ tumor cell subcluster enriched in the VTT head region, and functional assays demonstrated that CD74 significantly enhances ACC cell migration, invasion, and proliferation through activation of the JAK-STAT signaling pathway. Moreover, spatial and ligand-receptor analyses revealed that SPP1+ macrophages closely interact with CD74+ tumor cells via the SPP1-CD44 axis. Functional experiments confirmed that SPP1 secreted by macrophages potentiates CD74-induced JAK-STAT activation and malignant phenotypes. Collectively, we found that CD74+ tumor cells drive ACC progression under the regulation of the SPP1-CD44 signaling pathway in the vicinity of SPP1+ macrophages, thereby revealing a novel mechanistic axis with therapeutic potential.