垂体神经内分泌肿瘤（PitNET）通常具有侵袭性，并会发生远处转移，而目前的治疗方法难以治愈。然而，PitNET 攻击性的分子机制尚不清楚。发育多能性相关 4 (DPPA4) 被认为是一种干细胞调节基因，在某些癌症中过度表达，但其在 PitNET 攻击性背景下的功能尚不清楚。我们采用了大鼠和人类 PitNET 模型。在大鼠垂体瘤模型（RPT）中，我们使用产前酒精暴露（PAE）的雌性 Fischer 大鼠，这些大鼠在雌激素治疗后产生侵袭性 PitNETs，而在人垂体瘤（HPT）模型中，我们使用来自垂体瘤的侵袭性增殖细胞接受手术的患者。使用各种分子、细胞和表观遗传学技术来确定 DPPA4 在 PitNET 攻击性中的作用。我们发现，在 PAE 大鼠和人类患者的攻击性 PitNET 中，DPPA4 过表达与细胞干性因子增加相关。基因编辑实验表明，DPPA4 增加细胞干性和肿瘤侵袭性基因的表达，并促进 PitNET 细胞的增殖、定植、迁移和致瘤潜力。 ChIP 测定和受体拮抗研究表明，DPPA4 与典型的 WINT 启动子结合，并直接或间接增强 Wnt/β-catenin 对细胞干性、肿瘤生长和 PitNET 侵袭性的控制。表观遗传学研究表明组蛋白甲基转移酶参与 DPPA4 的酒精激活。这些发现支持 DPPA4 在肿瘤干性和侵袭性中的作用，并为调节这种干性调节因子治疗 PitNET 提供了临床前基本原理。© 作者 2024 年。已发表由牛津大学出版社代表神经肿瘤学会出版。

Pituitary neuroendocrine tumors, PitNETs, are often aggressive and precipitate in distant metastases that are refractory to current therapies. However, the molecular mechanism in PitNETs' aggressiveness is not well understood. Developmental pluripotency-associated 4 (DPPA4) is known as a stem cell regulatory gene and overexpressed in certain cancers, but its function in the context of PitNETs' aggressiveness is not known.We employed both rat and human models of PitNETs. In the rat pituitary tumor model (RPT), we used prenatal-alcohol-exposed (PAE) female Fischer rats which developed aggressive PitNETs following estrogen treatment, while in the human pituitary tumor (HPT) model, we used aggressively proliferative cells from pituitary tumors of patients undergone surgery. Various molecular, cellular, and epigenetic techniques were used to determine the role of DPPA4 in PitNETs' aggressiveness.We show that DPPA4 is overexpressed in association with increased cell stemness factors in aggressive PitNETs of PAE rats and of human patients. Gene-editing experiments demonstrate that DPPA4 increases the expression of cell stemness and tumor aggressiveness genes and promotes proliferation, colonization, migration, and tumorigenic potential of PitNET cells. ChIP assays and receptor antagonism studies reveal that DPPA4 binds to canonical WINTs promoters and increases directly or indirectly the Wnt/β-catenin control of cell stemness, tumor growth, and aggressiveness of PitNETs. Epigenetic studies show involvement of histone methyltransferase in alcohol activation of DPPA4.These findings support a role of DPPA4 in tumor stemness and aggressiveness and provide a preclinical rationale for modulating this stemness regulator for the treatment of PitNETs.© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.