2. Academic Validation
  3. METTL14 integrates tumor-derived SAM to drive parabrachial epigenetic rewiring in pancreatic cancer

METTL14 integrates tumor-derived SAM to drive parabrachial epigenetic rewiring in pancreatic cancer

  • Neuron. 2025 Nov 4:S0896-6273(25)00755-X. doi: 10.1016/j.neuron.2025.10.002.
Xiaohua Yang 1,  Xintong Wang 2,  Weicheng Lu 2,  Qingqing Ye 2,  Yongchun Li 2,  Xinyu Ma 2,  Yaqi Ye 2,  Xiangna Guo 2,  Guojun Chen 2,  Wenjun Xin 3,  Ting Xu 3,  Weian Zeng 2,  Jingdun Xie 4
Affiliations

Affiliations

  • 1 Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China; Guangdong Province Key Laboratory of Brain Function and Disease, Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road 2, Guangzhou 510080, P.R. China.
  • 2 Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China.
  • 3 Guangdong Province Key Laboratory of Brain Function and Disease, Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road 2, Guangzhou 510080, P.R. China.
  • 4 Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China. Electronic address: [email protected].
PMID: 41192426 DOI: 10.1016/j.neuron.2025.10.002
Abstract

Tumor-neural crosstalk drives Cancer progression and neurological symptoms, yet how tumors rewire brain circuits remains unclear. Here, we identified upregulated methyltransferase-like 14 (METTL14) in lateral parabrachial nucleus glutamatergic neurons (LPBNGlu) as a key regulator of pain-depression comorbidity in pancreatic ductal adenocarcinoma (PDAC) mice. METTL14 inhibition reversed PDAC-induced neuronal hyperexcitability and alleviated behavioral deficits. Mechanistically, METTL14 coordinated the tumor-derived S-adenosylmethionine (SAM) to promote N6-methyladenosine (m6A) modification of Adrenomedullin (ADM) mRNA, enhancing neuronal hyperactivation and potentiating LPBNGlu projections to the paraventricular thalamus (PVT) and lateral hypothalamus (LH). ADM suppression and chemogenetic or optogenetic silencing of LPBNGlu → PVTGlu/LHGlu circuits significantly mitigated comorbidity. Moreover, elevated circulating SAM in PDAC patients and mice amplifies this pathway. A methionine-restricted diet (MRD) reduced SAM levels, mitigating comorbidity and suppressing tumor growth. Our findings unveil the SAM-METTL14-ADM axis and LPBNGlu → PVTGlu/LHGlu neurocircuits in PDAC-induced brain remodeling, positioning MRD as a promising therapeutic strategy to improve patient outcomes.

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