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<p>The emerging field of cancer neuroscience has demonstrated great progress in revealing the crucial role of the nervous system in cancer initiation and progression. Pancreatic ductal adenocarcinoma (PDAC) is characterized by perineural invasion and modulated by autonomic (sympathetic and parasympathetic) and sensory innervations. Here, we further demonstrated that within the tumor microenvironment of PDAC, nociceptor neurons interacted with cancer-associated fibroblasts (CAFs) through calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF). This interaction led to the inhibition of interleukin-15 expression in CAFs, suppressing the infiltration and cytotoxic function of natural killer (NK) cells and thereby promoting PDAC progression and cancer pain. In PDAC patients, nociceptive innervation of tumor tissue is negatively correlated with the infiltration of NK cells while positively correlated with pain intensity. This association serves as an independent prognostic factor for both overall survival and relapse-free survival for PDAC patients. Our findings highlight the crucial regulation of NK cells by nociceptor neurons through interaction with CAFs in the development of PDAC. We also propose that targeting nociceptor neurons or CGRP signaling may offer a promising therapy for PDAC and cancer pain.</p>

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Nociceptor neurons promote PDAC progression and cancer pain by interaction with cancer-associated fibroblasts and suppression of natural killer cells

  • 期刊论文

  • 发表日期：

    2025年3月24日

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  • Kaiyuan Wang,
  • Bo Ni,
  • Yongjie Xie,
  • Zekun Li,
  • Limei Yuan,
  • Chenyang Meng,
  • Tiansuo Zhao,
  • Song Gao,
  • Chongbiao Huang,
  • Hongwei Wang,
  • Ying Ma,
  • Tianxing Zhou,
  • Yukuan Feng,
  • Antao Chang,
  • Chao Yang,
  • Jun Yu,
  • Wenwen Yu,
  • Fenglin Zang,
  • Yanhui Zhang,
  • Ru-Rong Ji,
  • Xiuchao Wang,
  • Jihui Hao

摘要

The emerging field of cancer neuroscience has demonstrated great progress in revealing the crucial role of the nervous system in cancer initiation and progression. Pancreatic ductal adenocarcinoma (PDAC) is characterized by perineural invasion and modulated by autonomic (sympathetic and parasympathetic) and sensory innervations. Here, we further demonstrated that within the tumor microenvironment of PDAC, nociceptor neurons interacted with cancer-associated fibroblasts (CAFs) through calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF). This interaction led to the inhibition of interleukin-15 expression in CAFs, suppressing the infiltration and cytotoxic function of natural killer (NK) cells and thereby promoting PDAC progression and cancer pain. In PDAC patients, nociceptive innervation of tumor tissue is negatively correlated with the infiltration of NK cells while positively correlated with pain intensity. This association serves as an independent prognostic factor for both overall survival and relapse-free survival for PDAC patients. Our findings highlight the crucial regulation of NK cells by nociceptor neurons through interaction with CAFs in the development of PDAC. We also propose that targeting nociceptor neurons or CGRP signaling may offer a promising therapy for PDAC and cancer pain.