胰腺癌 z-bio 2025-07-03 2947

　　Pancreatic cancer is a gastrointestinal tumor with a very high degree of malignancy, and pancreatic ductal adenocarcinoma (PDAC) accounts for more than 95%. Because of its low early diagnosis rate, it is mostly late when discovered, with low survival rate and poor prognosis, and is called the "king of cancer".

　　Previous studies have found that long-term stress can not only cause mental illness, damage cardiovascular health, but may also promote cancer development. However, the molecular mechanism of the progression of stress-driven symptoms is still unclear.

　　On May 26, 2025, Researcher Zheng Jian, Associate Researcher Huang Xudong and Academician Lin Dongxin, as co-corresponding authors, published a research paper entitled "Psychological stress-induced ALKBH5 deficiency promotes tumour independence and pancreatic cancer via extracellular vesicle transfer of RNA" in Nature Cell Biology, revealing new mechanisms of psychological stress promoting pancreatic cancer and proposing potential treatment strategies.

　　How to quietly “feed” pancreatic cancer?

　　For a long time, scientists have realized that being under psychological or physiological stress for a long time will not only easily cause mental problems such as anxiety and depression, but will also cause damage to the cardiovascular system and may accelerate the development of cancer. In this context, the study focuses on the association between psychological stress and progression of pancreatic cancer.

　　The researchers introduced three different types of stress stimuli in a mouse model of pancreatic cancer: restrained stress, chronic unpredictable stress, and painful-induced stress to observe their impact on tumor development. The results showed that all three stress forms significantly promote the development of pancreatic cancer: enlarged tumor volume; accelerated cancer cell proliferation; and enhanced innervation in the tumor microenvironment.

　　Further analysis found that these changes were closely related to an RNA demethylase called ALKBH5. ALKBH5 is a key enzyme that can regulate the level of m6A (N6-methyladenosine) modification on RNA, which affects the stability and function of RNA. Under stress stimulation, the sympathetic nerves in the mice were activated and released a large amount of norepinephrine, which in turn led to downregulation of ALKBH5 gene expression and the m6A modification level of RNA increased.

　　Interestingly, when the researchers artificially overexpressed ALKBH5, tumor growth was significantly inhibited, nerve infiltration was reduced, and the survival of mice was also significantly prolonged, indicating that ALKBH5 has a tumor suppressive effect.

　　The human body mainly relies on two pathways to cope with stress: the hypothalamus-pituitary-adrenal axis (HPA axis) and the sympathetic nervous system (SNS). Which pathway dominated the downward adjustment of ALKBH5? To understand this problem, the researchers conducted experimental interventions.

　　They first removed the adrenal glands of the mice and found that even without the effect of the HPA axis, the tumor still grew and the expression of ALKBH5 did not recover; but when they destroyed the sympathetic nerve, the tumor growth slowed down significantly and the expression of ALKBH5 rebounded; on the contrary, activation of the sympathetic nerve further inhibited the expression of ALKBH5. This suggests that stress affects pancreatic cancer development through the sympathetic nervous system rather than the adrenal pathway.

　　从“压力信号”到“肿瘤帮凶”

　　The study further found that norepinephrine, as the main transmitter of the sympathetic nerve, can bind to the β2 adrenaline receptor (ADRB2) on the surface of pancreatic cancer cells, activate downstream signaling pathways, reduce the level of histone H3K27ac modification, and thus inhibit the transcription of the ALKBH5 gene. Although ALKBH5 itself does not directly affect cancer cell division, it indirectly alters neural behavior in the tumor microenvironment by regulating RNA modification.

　　Specifically, after the decrease in ALKBH5 expression, the m6A modification level of RNA in pancreatic cancer cells increases, which is more likely to exist stably and is packaged into exosomes and released around the tumor.

　　These exosomes rich in m6A modification are then ingested by surrounding neurons, where RNA adsorbs miRNA through the "sponge effect" to relieve the inhibition of its target genes, thereby activate nerve growth-related pathways, promote tumor innervation, and ultimately promote cancer progress.

　　Finally, based on the idea of "blocking nerve-cancer cell signaling interaction", the research team screened out natural flavonoid compound fisetin from 20 membrane fusion inhibitors, which specifically blocked the absorption of exosomes by nerve cells, reduced tumor innervation, and increased the tumor growth inhibition rate in mice by 50% and extended the survival by 30%.

　　This discovery provides a new strategy for pancreatic cancer treatment with "anti-innervation", which is expected to combine psychological stress management with targeted treatment to break through the existing therapeutic bottlenecks.