Growth hormone-secreting pituitary neuroendocrine tumors can be pathologically classified into densely granulated (DGGH) and sparsely granulated types (SGGH). SGGH is more aggressive and associated with a poorer prognosis. While epigenetic regulation is vital in tumorigenesis and progression, the role of N6-methyladenosine (m6A) in aggressive behavior has yet to be elucidated. We performed m6A-sequencing on tumor samples from 8 DGGH and 8 SGGH patients, complemented by a suite of assays including ELISA, immuno-histochemistry, -blotting and -fluorescence, qPCR, MeRIP, RIP, and RNA stability experiments, aiming to delineate the influence of m6A on tumor behavior. We further assessed the therapeutic potential of targeted drugs using cell cultures, organoid models, and animal studies. We discovered a significant reduction of m6A levels in SGGH compared to DGGH, with an elevated expression of fat mass and obesity-associated protein (FTO), an m6A demethylase, in SGGH subtype. Series of in vivo and in vitro experiments demonstrated that FTO inhibition in tumor cells robustly diminishes hypoxia resistance, attenuates growth hormone secretion, and augments responsiveness to octreotide. Mechanically, FTO-mediated m6A demethylation destabilizes desmoplakin (DSP) mRNA, mediated by the m6A reader FMR1, leading to prohibited desmosome integrity and enhanced tumor hypoxia tolerance. Targeting the FTO-DSP-SSTR2 axis curtailed growth hormone secretion, therefor sensitizing tumors to octreotide therapy. Our study reveals the critical role of FTO in the aggressive growth hormone-secreting pituitary neuroendocrine tumors subtype and suggests FTO may represent a new therapeutic target for refractory/persistent SGGH.

中文翻译：

---

FTO介导的DSP m6A去甲基化促进分泌生长激素的垂体神经内分泌肿瘤的侵袭性亚型


分泌生长激素的垂体神经内分泌肿瘤在病理上可分为致密颗粒型（DGGH）和稀疏颗粒型（SGGH）。 SGGH 更具侵袭性，且预后较差。虽然表观遗传调控在肿瘤发生和进展中至关重要，但 N6-甲基腺苷 (m6A) 在攻击行为中的作用尚未阐明。我们对 8 名 DGGH 和 8 名 SGGH 患者的肿瘤样本进行了 m6A 测序，并辅以一系列测定，包括 ELISA、免疫组织化学、印迹和荧光、qPCR、MeRIP、RIP 和 RNA 稳定性实验，旨在描绘m6A 对肿瘤行为的影响。我们利用细胞培养、类器官模型和动物研究进一步评估了靶向药物的治疗潜力。我们发现，与 DGGH 相比，SGGH 中的 m6A 水平显着降低，并且 SGGH 亚型中脂肪量和肥胖相关蛋白 (FTO)（一种 m6A 去甲基酶）的表达升高。系列体内和体外实验表明，肿瘤细胞中的 FTO 抑制可显着降低耐缺氧性，减弱生长激素分泌，并增强对奥曲肽的反应性。从机械角度来说，FTO 介导的 m6A 去甲基化会破坏由 m6A 读取器 FMR1 介导的桥粒斑蛋白 (DSP) mRNA 的稳定性，从而导致桥粒完整性受到抑制并增强肿瘤的缺氧耐受性。靶向 FTO-DSP-SSTR2 轴可减少生长激素的分泌，从而使肿瘤对奥曲肽治疗敏感。我们的研究揭示了 FTO 在侵袭性生长激素分泌性垂体神经内分泌肿瘤亚型中的关键作用，并表明 FTO 可能代表难治性/持续性 SGGH 的新治疗靶点。