COL4A3 promotes invasion and acts as a biomarker in pituitary neuroendocrine tumor

Abstract Pituitary neuroendocrine tumors (PitNETs) present significant clinical challenges due to unpredictable invasive behavior and lack of reliable molecular predictors. While the extracellular matrix (ECM), particularly type IV collagen, has emerged as a critical mediator of tumor progression, its mechanistic role in PitNETs remains unclear. Through transcriptomic profiling of patient-derived PitNETs, functional assays in GH3 pituitary tumor cells, and orthotopic allograft models, we identified collagen type IV alpha 3 chain (COL4A3) as a key promoter of tumor invasion. Western blotting and flow cytometry revealed that COL4A3 was markedly upregulated in invasive PitNETs and promoted tumor cell proliferation, invasion, and survival both in vitro and in vivo. Mechanistically, COL4A3 knockdown reduced total FAK, PI3K, and AKT protein levels and altered ERK signaling, suggesting a possible link between COL4A3 and this pathway in promoting invasion, suppressing apoptosis, and driving cell cycle progression. Interestingly, serum COL4A3 levels were paradoxically lower in patients with invasive tumors, suggesting complex ECM remodeling dynamics during invasion that may reflect increased matrix degradation or altered systemic release patterns. These findings establish COL4A3 as a potential regulator of PitNET aggressiveness with dual utility as both a therapeutic target and a potential serum biomarker, offering new molecular insights into ECM-mediated tumor progression and opening avenues for precision diagnostics and treatment strategies.