Chaudhary Shaista, Das Ujjal, Jabbar Shaima, Gangisetty Omkaram, Rousseau Bénédicte, Hanft Simon, Sarkar Dipak K
The Endocrine Program, Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA.
Endocrinology and Animal Biosciences Graduate Program, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA.
Neuro Oncol. 2025 Jan 12;27(1):123-139. doi: 10.1093/neuonc/noae148.
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, we used prenatal-alcohol-exposed (PAE) female Fischer rats which developed aggressive PitNETs following estrogen treatment, while in the human pituitary tumor 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 the 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.
垂体神经内分泌肿瘤（PitNETs）通常具有侵袭性，并易发生远处转移，而目前的治疗方法对其难以奏效。然而，PitNETs侵袭性的分子机制尚不清楚。发育多能性相关蛋白4（DPPA4）是一种干细胞调节基因，在某些癌症中过度表达，但其在PitNETs侵袭性方面的作用尚不清楚。
我们采用了大鼠和人类PitNETs模型。在大鼠垂体肿瘤模型中，我们使用了产前酒精暴露（PAE）的雌性Fischer大鼠，这些大鼠在雌激素处理后会发生侵袭性PitNETs；而在人类垂体肿瘤模型中，我们使用了接受手术的垂体肿瘤患者的侵袭性增殖细胞。我们运用了各种分子、细胞和表观遗传技术来确定DPPA4在PitNETs侵袭性中的作用。
我们发现，在PAE大鼠和人类患者的侵袭性PitNETs中，DPPA4的表达上调，同时细胞干性因子增加。基因编辑实验表明，DPPA能够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。染色质免疫沉淀（ChIP）分析和受体拮抗研究表明，DPPA4与经典WNT启动子结合，直接或间接增强WNT/β-连环蛋白对PitNET细胞干性、肿瘤生长和侵袭性的调控。表观遗传学研究表明，组蛋白甲基转移酶参与了酒精对DPPA4的激活作用。
这些发现支持了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以治疗PitNETs提供了临床前的理论依据。
