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2024

A team study by Jiang Xiaobing of Sun Yat-sen University reveals the key role of FTO in subtypes of invasive growth hormone secreting pituitary neuroendocrine tumors

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Growth hormone secreting pituitary neuroendocrine tumors can be divided into dense granular type (DGGH) and sparse granular type (SGGH). SGGH is more aggressive and has a poor prognosis. Although epigenetic regulation is critical in tumorigenesis and progression, N⁶-Methyl adenosine (m⁶A) role in aggressive behavior has not been elucidated.

On September 20, 2024, Sun Yat-sen University Jiang Xiaobing, Zuo Zhixiang, Zhang Jialiang and Guangdong Pharmaceutical University Liu Aiqun jointly communicatedMolecular Cancer Online is titled“FTO mediated DSP m⁶A demethylation promote an aggressive subtype of growth hormone-secreting pituitary neuroendocrine tumors”The research paper,The studyReveals the critical role of FTO in the subtype of invasive growth hormone secreting pituitary neuroendocrine tumors and suggests that FTO may be a new therapeutic target for refractory/persistent SGGH.

Tumor samples from 8 patients with DGGH and 8 patients with SGGH were m⁶A sequencing further evaluated the therapeutic potential of targeted drugs through cell culture, organoid models and animal experiments. The study found that compared with DGGH, m in SGGH⁶A levels were significantly reduced, fat mass and obesity-associated protein (FTO) in the SGGH subtype (a m⁶A demethylase) increased expression. A series of in vivo and in vitro experiments have shown that the inhibitory effect of FTO in tumor cells can significantly reduce the ability of hypoxia tolerance, weaken the secretion of growth hormone, and enhance the response to octreotide. Mechanically, FTO-mediated m⁶A demethylation disrupts the demethylation by m⁶A reader FMR1 mediates the stability of desmogram protein (DSP) mRNA, leading to the destruction of desmogram integrity and enhanced tumor hypoxia tolerance.Targeting the FTO-DSP-SSTR2 axis reduces growth hormone secretion, thereby sensitizing tumors to octreotide therapy.

Growth hormone-secreting pituitary neuroendocrine tumors account for about 10% of pituitary neuroendocrine tumors (PitNETs) and are one of the most common intracranial tumors in adults.Growth hormone-secreting pituitary neuroendocrine tumors are associated with significant comorbidities and an increased risk of death. Long-term exposure to excess growth hormone can cause harmful effects on various systems and organs, including the cardiovascular, respiratory, and musculoskeletal systems. In addition, patients with GH-secreting pituitary neuroendocrine tumors have a significantly higher risk of developing colorectal, breast, and thyroid cancers. As a result, their long-term quality of life is generally poor, shortening their lifespan by about 30% compared to the general population. According to the 2022 WHO PitNETs classification, growth hormone-secreting pituitary neuroendocrine tumors belong to the PIT1 lineage and are further divided into dense granular (DGGH) and sparse granular (SGGH) subtypes. DGGH usually shows a non-invasive growth pattern with a good prognosis. SGGHs are characterized by aggressive growth, resistance to regular therapy, and poor prognosis, and are classified as refractory/persistent growth hormone-secreting pituitary neuroendocrine tumors. Despite recent advances in endoscopic techniques, about 15% of growth hormone-secreting pituitary neuroendocrine tumors invade the cavernous sinus and bone without biochemical cure, even with optimal postoperative radiation therapy and newer medical therapy. Therefore, it is of great significance to explore new drugs for the treatment of refractory/persistent growth hormone-secreting pituitary neuroendocrine tumors.The different biological patterns of DGGH and SGGH provide a suitable model for studying the pathogenesis of aggressive behavior.

Desmosemes are composed of a variety of connexins and are important intercellular junctions that promote intercellular communication and maintain junction integrity.Studies have shown that desmoses play an important role in the development of various malignant tumors, including gastric cancer, colorectal cancer and breast cancer. Conversely, loss or attenuation of desmosome structure promotes tumor invasion and metastasis. In the desmosome complex, desmogrin (DSP) is the core protein at cell junctions, interacting with other proteins such as thromboglobin, desmogrin, and hemophagocytic platelet protein. In heart disease, DSP gene mutations impair desmosome function and promote the development of arrhythmogenic cardiomyopathy. In addition, the loss of DSP will destroy the intercellular connection between tumor cells, and promote tumor cell invasion and metastasis.A previous study found that gene transcripts related to desmosome structure and function were persistently down-regulated in SGGH, suggesting that desmosomes play a key role in the formation of the aggressive phenotype.

N⁶-Methyl adenosine (m⁶A) The modifications are the most abundant endogenous RNA modifications in eukaryotes.It is reported to be involved in a variety of physiological processes, including embryonic development, immune system maturation, and neural development. m⁶A recruits specific reading proteins to target RNA through the action of RNA methyltransferase and demethylase, thus affecting the stability, translation, alternative splicing and other functions of RNA. Recent studies have shown that m⁶Dysregulation of A is associated with tumorigenesis, invasion and the formation of cell adhesion. For example, m⁶A demethylase FTO by m⁶A-FOS-IGF₂BP₁_/2The dependent way affects the metastasis and invasion of Epstein-Barr virus-associated gastric cancer, and provides biomarkers for the prediction and treatment of gastric cancer metastasis. FMR1 is a new type of m⁶A reader, upregulated expression in colorectal cancer (CRC) and by identifying m in EGFR mRNA⁶A modification site, which plays a key role in promoting the proliferation and metastasis of colorectal cancer cells. In addition, METTL14 affects neuronal activity and pain sensitivity in chemotherapy-induced neuropathic pain through the GluN2A subunit of NMDAR, highlighting a potential therapeutic target for pain management in cancer therapy. However, few studies have shown that METTL3 is upregulated in growth hormone-secreting pituitary neuroendocrine tumors and promotes tumor cell proliferation and invasion.m⁶The role of A in the pathogenesis of growth hormone-secreting pituitary neuroendocrine tumors remains to be elucidated.

Previous studies have revealed the potential function of epigenetic regulation in the progression of invasive PitNETs.On this basis, further analysis of m in DGGH and SGGH samples⁶Modification of A, exploring m⁶Role of A modification in regulating the invasive behavior of growth hormone-secreting pituitary neuroendocrine tumors. study found a different m between DGGH and SGGH⁶A spectrum, mainly regulated by FTO. FTO promotes hypoxia tolerance, octreotide resistance, and growth hormone secretion in growth hormone-secreting pituitary neuroendocrine tumors by reducing the stability of DSP mRNA, a key component of desmosome, and disrupting the structure of desmosome. In conclusion, the study proposes a new approach to distinguish between subtypes of somatotropin-secreting pituitary neuroendocrine tumors and reveals the underlying pathogenesis of their aggressive growth pattern.Components in this pathway represent potential therapeutic targets for refractory/persistent GH-secreting pituitary neuroendocrine tumors.