bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2025–09–28
eight papers selected by
Maksym V. Kopanitsa, Charles River Laboratories
  1. Sensory neurons drive pancreatic cancer progression through glutamatergic neuron-cancer pseudo-synapses.
  2. Tumor Innervation: From Bystander to Emerging Therapeutic Target for Cancer.
  3. The impact of perineural invasion on prognosis in esophageal cancer patients after surgery: a systematic review and meta-analysis.
  4. Correlation between perineural invasion and clinicopathological characteristics in pancreatic cancer.
  5. Perineural Invasion in Pancreatic Ductal Adenocarcinoma: Recapitulating Its Importance and Defining Future Directions.
  6. Steroid Receptor Coactivator-1 Drives Tumor-Associated Macrophage Reprogramming by Mediating MMP12 Transcription in Pancreatic Cancer Perineural Invasion.
  7. Dynamic interplay of neuroendocrine signaling and immuno-surveillance in tumor niche remodeling.
  8. [Neuro-immune interactions in the tumor microenvironment: from mechanisms to precision therapy].
  1. Cancer Cell. 2025 Sep 25. pii: S1535-6108(25)00395-2. [Epub ahead of print]
    Sensory neurons drive pancreatic cancer progression through glutamatergic neuron-cancer pseudo-synapses.
    Lei Ren, Chunfeng Liu, Kaan Çifcibaşı, Markus Ballmann, Gerhard Rammes, Carmen Mota Reyes, Sergey Tokalov, Andreas Klingl, Jennifer Grünert, Keshav Goyal, Peter H Neckel, Ulrich Mattheus, Benjamin Schoeps, Saliha Elif Yıldızhan, Osman Ugur Sezerman, Nedim Can Cevik, Elif Arik Sever, Didem Karakas, Okan Safak, Katja Steiger, Alexander Muckenhuber, Kıvanç Görgülü, Zongyao Chen, JingCheng Zhang, Linhan Ye, Mohammed Inayatullah Maula Ali, Vijay K Tiwari, Nataliya Romanyuk, Florian Giesert, Dieter Saur, Roland Rad, Roland M Schmid, Hana Algül, Achim Krüger, Helmut Friess, Güralp O Ceyhan, Rouzanna Istvanffy, Ihsan Ekin Demir.
      Cancers thrive on neuronal input. Here, we demonstrate the presence of pseudo-synaptic connections between sensory nerve endings and cancer cells in an extracerebral cancer, i.e., pancreatic ductal adenocarcinoma (PDAC). These synaptic sites exhibit a selective enrichment of the glutamatergic N-methyl-D-aspartate receptor (NMDA) receptor subunit NMDAR2D (GRIN2D) on the cancer cells, which turns PDAC cells responsive to neuron-derived glutamate and promotes tumor growth and spread. Intriguingly, neurons transform a subset of co-cultured PDAC cells into calcium-responsive cells via GRIN2D-type glutamate receptors at the neuron-cancer pseudo-synapses. We found that the expression of this subunit is due to the increased glutamate availability provided by sensory innervation in a neurotrophic feedforward loop. Moreover, interference with the glutamate-GRIN2D signaling at these neuron-cancer pseudo-synapses markedly improved survival in vivo. This discovery of peripheral cancer-neuron pseudo-synapses may provide an opportunity for cancer-neuroscience-instructed oncological therapies.
    Keywords:  GRIN2D; L-glutamate; NMDAR; glutamatergic receptor; innervation; neural invasion; pancreatic cancer; synapse
    DOI:  https://doi.org/10.1016/j.ccell.2025.09.003
  2. Int J Mol Sci. 2025 Sep 22. pii: 9257. [Epub ahead of print]26(18):
    Tumor Innervation: From Bystander to Emerging Therapeutic Target for Cancer.
    Zoey Zeyuan Ji, Max Kam-Kwan Chan, Philip Chiu-Tsun Tang, Calvin Sze-Hang Ng, Chunjie Li, Dongmei Zhang, David J Nikolic-Paterson, Ka-Fai To, Xiaohua Jiang, Patrick Ming-Kuen Tang.
      Innervation is ubiquitous in diseased tissues, including cancer. Increasing evidence suggests that innervation not only plays a direct role in cancer pain, but is also closely related to disease progression, including cancer growth, metastasis, and drug resistance. At the molecular level, tumor-associated nerves can interact with cancer cells and the tumor microenvironment through neurotrophic factors, thereby promoting tumor occurrence and development, and represent a potential intervention for solid tumors with nerve enrichment. By dissecting the transcriptome dynamics of cancer-associated neurons with single cell resolution, numbers of novel therapeutic targets for tumor denervation have been uncovered, including a novel phenomenon-Macrophage to Neuron-like cell Transition (MNT). This review systematically summarizes the latest research findings of tumor denervation, from molecular mechanisms to the innovative denervation strategies, paving the way for novel, safe, and effective cancer treatments in the clinic.
    Keywords:  denervation therapy; tumor innervation; tumor–nerve crosstalk
    DOI:  https://doi.org/10.3390/ijms26189257
  3. Front Oncol. 2025 ;15 1629335
    The impact of perineural invasion on prognosis in esophageal cancer patients after surgery: a systematic review and meta-analysis.
    Jicheng Xiong, Shuoming Liang, Simiao Lu, Hainan Chen, Ziwei Wang, Hao Meng, Yi Zhu, Yongtao Han, Xuefeng Leng.
       Objective: This study aims to update the prognostic value of perineural invasion(PNI) in various subgroups of esophageal cancer patients.
    Methods: We searched databases including PubMed, Scopus, Wiley, Web of Science, and Embase for full-text articles published in English on esophageal cancer related to PNI. The search was conducted up to January 1, 2024. We summarized the hazard ratios (HR) and 95% confidence intervals (CI) for overall survival (OS), disease-free survival (DFS), as well as recurrence and metastasis, to assess the prognostic value of PNI in patients with esophageal cancer.
    Results: A total of 38 eligible studies were ultimately included. Thirty-two studies, encompassing a total of 7157 patients, reported the correlation between PNI and OS. The results indicated that PNI is significantly associated with poor OS in esophageal cancer patients (HR = 1.54, 95% CI: 1.41-1.68, P < 0.00001). Eleven studies, including a total of 2224 patients, reported the correlation between PNI and DFS. These studies found that PNI is significantly associated with poor DFS (HR = 1.43, 95% CI: 1.25-1.62, P < 0.00001). Three studies, including a total of 1125 patients, reported no correlation between PNI and recurrence (HR = 1.17, 95% CI: 0.62-2.18, P = 0.63). Two studies, including a total of 556 patients, reported a correlation between PNI and distant metastasis (HR = 2.19, 95% CI: 1.02-4.73, P = 0.04). Further subgroup analysis revealed that PNI is an independent prognostic factor for esophageal squamous cell carcinoma (ESCC) (OS: HR=1.62, 95%CI: 1.35-1.94, P<0.00001; DFS: HR=1.28, 95%CI: 1.03-1.59, P=0.03); however, in esophageal adenocarcinoma, PNI is not associated with OS or DFS (OS: HR=1.23, 95%CI: 1.00-1.53, P=0.05; DFS: HR=1.65, 95%CI: 0.95-2.87, P=0.08). PNI positivity is associated with unfavorable outcomes, irrespective of neoadjuvant therapy receipt. In the non-Asian subgroup, PNI is not statistically significant for poor DFS prognosis.
    Conclusion: PNI is a histological marker of aggressive disease and can serve as an independent prognostic factor for patients with esophageal cancer. PNI positivity can predict poor outcomes in ESCC, but its role as a prognostic indicator for adenocarcinoma requires further investigation.
    Keywords:  distant metastasis; esophageal cancer; perineural invasion; prognosis; recurrence
    DOI:  https://doi.org/10.3389/fonc.2025.1629335
  4. World J Gastrointest Oncol. 2025 Sep 15. 17(9): 108277
    Correlation between perineural invasion and clinicopathological characteristics in pancreatic cancer.
    Xiao-Liang Lu, Chuang Ge, Ruo-Chen Wang, Hong Zang.
       BACKGROUND: Perineural invasion (PNI) is common in pancreatic cancer (PC) and is associated with poor prognosis.
    AIM: To investigate the correlation between PNI and clinical pathological features in PC.
    METHODS: Patients were retrospectively divided into non-neural invasion and neural invasion groups based on PNI. Differences in tumor location, size, carbohydrate antigen 19-9 (CA19-9) level, overall survival, abdominal pain, pathological type, differentiation, and lymph node invasion were compared. Correlation and logistic regression analyses were performed, and a predictive model was constructed.
    RESULTS: The neural invasion group had a higher proportion of tumors in the head, larger size, higher CA19-9 levels, lower survival rates, more abdominal pain, and more lymph node invasion. Pancreatic ductal adenocarcinoma and higher differentiation were more common in the neural invasion group. Tumor location, survival, and differentiation were negatively correlated, while size, CA19-9 level, abdominal pain, and lymph node invasion were positively correlated with neural invasion. Tumor location, size, CA19-9 level, abdominal pain, differentiation, and lymph node invasion were independent risk factors. The predictive model showed good consistency with actual occurrence rates.
    CONCLUSION: Tumor location, size, CA19-9 level, abdominal pain, differentiation, and lymph node invasion are important factors in neural invasion and tumor progression in PC.
    Keywords:  Clinicopathological characteristics; Pancreatic cancer; Perineural invasion; Predictive model; Risk factors
    DOI:  https://doi.org/10.4251/wjgo.v17.i9.108277
  5. United European Gastroenterol J. 2025 Sep 22.
    Perineural Invasion in Pancreatic Ductal Adenocarcinoma: Recapitulating Its Importance and Defining Future Directions.
    TRANSPAN PNI Group
      Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, mainly due to its aggressive nature, early metastasis, diagnosis at late stages, and limited response to systemic anticancer therapy. Perineural invasion (PNI), defined as the infiltration of neoplastic cells along nerve fibers and within nerve sheaths, is emerging as a critical determinant of PDAC aggressiveness. This position paper by the TRANSPAN PNI Group on Perineural Invasion synthesizes current evidence on the molecular features and clinical implications of PNI in PDAC, compares its prognostic significance in other malignancies, and describes novel biomarker strategies including potential therapeutic interventions.
    Keywords:  biomarkers; pancreatic cancer; pancreatic ductal adenocarcinoma; perineural invasion; prognostic marker; therapeutic strategies; tumor aggressiveness
    DOI:  https://doi.org/10.1002/ueg2.70118
  6. Adv Sci (Weinh). 2025 Sep 23. e16575
    Steroid Receptor Coactivator-1 Drives Tumor-Associated Macrophage Reprogramming by Mediating MMP12 Transcription in Pancreatic Cancer Perineural Invasion.
    Ke Cheng, Liang Liu, Miaomiao Gong, Yuke Ji, Chunmei Bai, Xiangqian Guo, Hui Chen, Jinjin Pan, Ying Zhang, Yuhui Yuan.
      Perineural invasion (PNI) is a hallmark of pancreatic cancer aggressiveness. However, the feasibility of manipulating tumor-associated macrophage (TAM) reprogramming to influence PNI development remains unclear. Methods: Using in vitro (tumor-DRG co-culture) and in vivo (sciatic nerve injection) models coupled with protein identification by liquid chromatography-mass spectrometry (LC-MS) and ChIP-seq, the role of steroid receptor coactivator-1 (SRC-1) is investigated in TAM reprogramming and PNI. SRC-1 is up-regulated in TAMs and promotes PNI by binding to signal transducer and activator of transcription 1(STAT1) to enhance matrix metallopeptidase 12 (MMP12) transcription. SRC-1 knockdown attenuated M2-like characteristics in TAMs, reduced MMP12 secretion, and suppressed PNI. Importantly, blocking the SRC-1/STAT1/MMP12 axis (using SRC-1-KO TAMs or MMP12 inhibitors) attenuated PNI progression in vivo. SRC-1 reprograms TAMs via STAT1-mediated MMP12 activation to facilitate PNI. Targeting SRC-1 disrupts this axis and presents a novel therapeutic strategy against PNI in pancreatic cancer.
    Keywords:  pancreatic cancer; perineural invasion; steroid coactivator receptor‐1; tumor associated macrophages
    DOI:  https://doi.org/10.1002/advs.202416575
  7. Crit Rev Oncol Hematol. 2025 Sep 18. pii: S1040-8428(25)00346-4. [Epub ahead of print]216 104958
    Dynamic interplay of neuroendocrine signaling and immuno-surveillance in tumor niche remodeling.
    Nuo Xu, Saiyan Bian, Pin Lyu, Xuyang He, Wenjie Zheng.
      The complex crosstalk between the nervous system and the tumor immune microenvironment (TIME) plays a key role in cancer progression, immune evasion, and therapy resistance. This review summarizes and critically examines bidirectional neuroimmune interactions within the TIME, focusing on how neural elements shape immune responses and how immune signals remodel neural circuits. Neurotransmitters, neuropeptides, and stress hormones such as norepinephrine and cortisol modulate dendritic-cell priming, natural killer (NK) and CD8⁺ T-cell cytotoxicity, and myeloid polarization, thereby establishing immunosuppression that supports tumor growth and metastasis. We also highlight how tumor-derived cues drive tumor-associated neurogenesis and nerve ingrowth, which reinforces metastasis through neural remodeling and immune regulation. In addition, we discuss therapeutic strategies that target these pathways, including β-adrenergic blockade, calcitonin gene-related peptide (CGRP) receptor antagonism, and inhibition of neurotrophic factors such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), as avenues to improve cancer treatment. Combining immune checkpoint inhibitors (ICIs) with neuromodulation is being investigated as a means to overcome drug resistance and enhance clinical benefit. Future work should apply spatially resolved and molecular technologies to define these circuits in situ and to guide biomarker-driven, patient-tailored multimodal therapies.
    Keywords:  Cancer immunotherapy; Crosstalk; Immunity; The nervous system; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.104958
  8. Zhonghua Wei Chang Wai Ke Za Zhi. 2025 Sep 25. 28(9): 1080-1086
    [Neuro-immune interactions in the tumor microenvironment: from mechanisms to precision therapy].
    Y J Zhang, T P Luo, F L Liu.
      The nervous system, as the core hub of physiological regulation in the human body, plays a key role in the tumor microenvironment through the neuro-immune-tumor axis. Studies have shown that tumor-infiltrating nerve fibers regulate immune cell functions by releasing neurotransmitters, while immune cells can feedback and modulate neuronal activity, forming a dynamic bidirectional interaction network. The emerging field of cancer neuroimmunology focuses on the complex dialogue mechanisms between the nervous and immune systems in the tumor microenvironment. In-depth analysis of the neuro-immune interaction network not only provides new perspectives for understanding tumor immune escape, but also lays the theoretical foundation for developing novel combination therapies targeting the neuro-immune axis, potentially providing breakthrough strategies to overcome resistance to current immunotherapies.
    DOI:  https://doi.org/10.3760/cma.j.cn441530-20250826-00318
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