bims-netuvo 2025-10-26 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2025–10–26
eleven papers selected by
Maksym V. Kopanitsa, Charles River Laboratories

Neuroscience in prostate cancer.
Functional pseudo-synapses: A new nexus in extracranial cancer.
Sickness and the brain.
Single-cell sequencing uncovers sensory neuron-mediated CGRP signaling as a driver of sarcoma progression.
KRAS/ACTN4/p65-NR2A axis mediates glutamine-glutamate metabolic coupling between schwann cells and pancreatic cancer promoting perineural invasion.
Pain - related methylation driver genes affect the prognosis of pancreatic cancer patients by altering immune function and perineural infiltration.
Na+/K+-ATPase Modulates Purinergic P2X3 Receptor Function to Drive Bone Cancer Pain.
A Seer-Based Analysis of Survival Predictors in Stage I Colorectal Adenocarcinomas.
Schwann cells drive tumor progression through neuro-tumor crosstalk.
Distinct Imaging Features of Peripheral Nerve Sheath Tumours in NF2-Related Schwannomatosis: A Case Report.
Schwannoma of the colon presenting as a submucosal lesion: diagnostic challenge and surgical management.

Prostate Cancer Prostatic Dis. 2025 Oct 18.

Neuroscience in prostate cancer.

Ziteng Liu, Qiang Peng, Yuliang Wang, Peter Ka-Fung Chiu, Jeremy Yuen-Chun Teoh, Rongjiang Wang, Xiaodong Liu, Dinglan Wu, Chi-Fai Ng.

BACKGROUND: Emerging evidence in cancer neuroscience indicates that the nervous system interacts directly or indirectly with cancer cells, promoting tumor progression. The prostate gland contains an extensive neural network essential for regulating key physiological functions of prostate cells, and the significant neural distribution observed in prostate cancer highlights its critical role in driving cancer pathogenesis. Unfortunately, Comprehensive reviews systematically summarizing progress in cancer neuroscience for prostate cancer are currently lacking.
METHOD: We synthesize existing research on interactions between the nervous system and prostate cancer cells, explore the neural distribution within the prostate, and evaluate the impact of neural innervation on prostate cancer development and progression. Additionally, we also assess the potential neural regulation mechanisms in neuroendocrine prostate cancer (NEPC).
RESULT: We found that neural interactions significantly influence prostate cancer development. Neural circuitry within the tumor microenvironment drives progression and contributes to the aggressiveness of lethal subtypes like NEPC. Targeting neuromodulation emerges as a promising therapeutic approach, potentially allowing the repurposing of established medications for treating advanced tumors.
CONCLUSION: Neuromodulation offers a promising therapeutic option for advanced prostate cancer, particularly NEPC, which faces limited treatment options. However, further research is necessary to fully understand the neural regulatory mechanisms involved in prostate cancer development and to identify new therapeutic targets and strategies for advanced stages.

DOI: https://doi.org/10.1038/s41391-025-01042-y
Cancer Cell. 2025 Oct 23. pii: S1535-6108(25)00407-6. [Epub ahead of print]

Functional pseudo-synapses: A new nexus in extracranial cancer.

Xiaofei Zhi, Puran Zhang, Timothy C Wang.

Functional cancer-to-neuron synapse-like connections are recognized as essential structures and hallmarks of both intracranial and extracranial tumors. In this issue of Cancer Cell, Ren et al. present high-resolution EM structures of pseudo-synaptic connections between sensory nerves and pancreatic ductal adenocarcinoma (PDAC).

DOI: https://doi.org/10.1016/j.ccell.2025.10.001
Curr Biol. 2025 Oct 20. pii: S0960-9822(25)01116-9. [Epub ahead of print]35(20): R973-R979

Sickness and the brain.

Zuri A Sullivan, Catherine Dulac.

The brain was once believed to be immune privileged, sequestered from peripheral inflammatory signals and pathogens, but it is now clear that bidirectional communication between the immune and nervous systems exists, serving as an integral part of animal physiology and behavior that shapes health and disease. In peripheral tissues, such as the gut, skin, and lungs, sensory neurons and tissue-resident immune cells communicate via soluble signals to fight infection. The field of cancer immunology has been bolstered by the discovery of numerous interactions between the nervous system and immune surveillance of cancer that have significant implications for human health. Similarly, the landscape of immune cells in the brain continues to expand and reveal new interactions with non-neuronal as well as neuronal cells that influence development, aging, and importantly, animal behavior. In this primer, we focus on sickness behavior as a prototypical example of reciprocal communication between the brain and body.

DOI: https://doi.org/10.1016/j.cub.2025.08.050
Proc Natl Acad Sci U S A. 2025 Oct 28. 122(43): e2500161122

Single-cell sequencing uncovers sensory neuron-mediated CGRP signaling as a driver of sarcoma progression.

Sowmya Ramesh, Qizhi Qin, Zhao Li, Masnsen Cherief, Lingke Zhong, Mary Archer, Xin Xing, Neelima Thottappillil, Devadutta Balaji, Sam Bae, Mario Gomez-Salazar, Mingxin Xu, Manyu Zhu, Ankit Uniyal, Leslie Chang, Khadijah Mazhar, Monisha Mittal, Alexander Birbrair, Edward F McCarthy, Carol D Morris, Benjamin Levi, Yun Guan, Thomas L Clemens, Theodore J Price, Aaron W James.

  Bone pain is a presenting feature of bone cancers such as osteosarcoma (OS), relayed by skeletal-innervating peripheral afferent neurons. Potential functions of tumor-associated sensory neurons in bone cancers beyond pain sensation are unknown. To uncover neural regulatory functions, a chemical-genetic approach in mice with a knock-in allele for TrkA was used to functionally perturb sensory nerve innervation during OS growth and disease progression. TrkA inhibition in transgenic mice led to significant reductions in sarcoma-associated sensory innervation and vascularization, skewed tumor associated macrophage polarization, reduced tumor growth and metastasis, and prolonged overall survival. Single-cell transcriptomics revealed that sarcoma denervation was associated with phenotypic alterations in both OS tumor cells and cells within the tumor microenvironment, and with reduced calcitonin gene-related peptide (CGRP) and vascular endothelial growth factor (VEGF) signaling. Multimodal and multiomics analyses of human OS bone samples further implicated peripheral innervation and neurotrophin signaling in OS tumor biology. Next and in two parallel approaches to inhibit nerve ingrowth, we repurposed FDA-approved bupivacaine liposomes and separately blocked CGRP signaling using FDA-approved Rimegepant. Both strategies led to significant reductions in sarcoma growth, vascularity, and sarcoma-induced hyperalgesia. In sum, TrkA-expressing peripheral neurons positively regulate key aspects of OS progression and sensory neural inhibition disrupts CGRP signaling within the sarcoma microenvironment leading to significantly reduced tumor growth and improved survival. These data suggest that interventions to prevent pathological innervation of OS represent an adjunctive therapy to improve clinical outcomes and survival.

Keywords:  neuropathic pain; sarcoma; skeletal innervation; tropomyosin receptor kinase A; vascularity

DOI:  https://doi.org/10.1073/pnas.2500161122
J Adv Res. 2025 Oct 22. pii: S2090-1232(25)00826-4. [Epub ahead of print]

KRAS/ACTN4/p65-NR2A axis mediates glutamine-glutamate metabolic coupling between schwann cells and pancreatic cancer promoting perineural invasion.

Zhenfeng Tian, Mingxin Su, Miao Yu, Enlai Huang, Bingrong Hu, Yinting Chen.

   INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) exhibits aggressive perineural invasion (PNI), a hallmark of poor prognosis observed in 70-100% of cases. Schwann cells (SCs), key components of the tumor microenvironment, drive PNI via multiple pathways, yet the underlying mechanisms remain unclear.
OBJECTIVES: This study investigates the hypothesis that PDAC cells and SCs establish a glutamine-glutamate metabolic symbiosis to fuel PNI.
METHODS: Integrated approaches, including LC-MS metabolomics, isotopic tracing, co-culture systems, and in vivo models, were employed to analyze bidirectional metabolite exchange. Molecular assays and functional studies elucidated signaling pathways. The therapeutic potential of targeting glutamine transporters (SLC1A5/SLC7A5) and glutamate receptor NR2A was tested using inhibitors V9302 and PEAQX.
RESULTS: SCs secreted glutamine, which PDAC cells internalized via SLC1A5 and converted to glutamate. Glutamate activated SCs through NR2A, inducing ROS/NRF2-expression and upregulating glutamine synthetase (GS) and GLT-1, thereby regenerating glutamine to sustain the metabolic loop. KRAS-ACTN4-p65 signaling amplified this cycle by transcriptionally activating SLC1A5/SLC7A5 and GLS, while leucine uptake via SLC7A5 activated mTORC1 to promote invasion and PNI. In vivo, dual inhibition of SLC1A5/SLC7A5 (V9302) and NR2A (PEAQX) synergistically reduced tumor growth, PNI length, and improved sciatic nerve function in mice.
CONCLUSION: This study identifies a reciprocal glutamine-glutamate metabolic symbiosis between PDAC cells and SCs as a driver of PNI, orchestrated by KRAS-ACTN4-NF-κB signaling and glutamate-NR2A-ROS-NRF2 pathways. Disrupting this axis with V9302 and PEAQX offers a novel therapeutic strategy to target PDAC's metabolic adaptability and neurotrophic microenvironment.

Keywords:  Glutamate; Glutamine; Pancreatic cancer; Perineural invasion; Schwann cells

DOI:  https://doi.org/10.1016/j.jare.2025.10.030
Front Genet. 2025 ;16 1600883

Pain - related methylation driver genes affect the prognosis of pancreatic cancer patients by altering immune function and perineural infiltration.

Chencheng Zhang, Weiwei Xu, Xudong Chen, Xingdan Wang, Xiaopeng Cui, Wenjing Zhao.

   Background: The malignant progression of pancreatic cancer (PC) is frequently accompanied by intractable pain mediated through perineural invasion (PNI), yet the underlying epigenetic regulatory mechanisms remain elusive.This study aims to elucidate the role of DNA methylation in the pathogenesis of PC pain, including its interactive effects with the nervous and immune systems.
Methods: Integrating multi-omics data from TCGA-PAAD (Pancreatic adenocarcinoma), we identified methylation driver genes (MDGs) using the MethylMix algorithm. By intersecting MDGs with pain-related gene sets and conducting multi-step regression modeling, we established a five-gene prognostic signature (PSMB8/COL17A1/BICC1/CTRC/TRIP13). Next, in order to elucidate the underlying mechanisms, we conducted differential expression analysis, protein-protein interaction network analysis, functional enrichment analysis, and single-cell sequencing. Additionally, we quantified immune infiltration using CIBERSORT and TIMER.
Results: Pain-related MDGs are enriched in immune regulation, extracellular matrix reorganization, and cation channel activity, constituting the "immune-neural axis" of epigenetic regulation. The prognostic five-gene signature significantly stratifies patient survival risk (HR = 3.83, p = 1.4e-8), with its methylation levels positively correlated with CD4+ T cell infiltration and negatively correlated with dendritic cells. Model-derived differentially expressed genes exhibited dual immune-neural tropism at single-cell resolution, prominently enriched in presynaptic signaling and synaptic vesicle cycling. Mechanistically, MDGs orchestrate pain progression through PNI-associated neural remodeling and K+ channel-mediated neuronal hypersensitization.
Conclusion: This study establishes a visceral pain model centered on pancreatic parenchymal nociception rather than secondary neural effects, and for the first time proposes an interconnected regulatory network linking epigenetic modifications, immune reprogramming, and neural plasticity, revealing dual pain pathogenesis mechanisms: (1) immune microenvironment reshaping that potentiates neuroinflammation, and (2) direct ion channel regulation enhancing neuronal excitability. These findings provide a mechanistic foundation for developing methylation-based prognostic biomarkers and multimodal analgesic therapeutic strategies targeting the immuno-neural nexus.

Keywords:  DNA methylation; immune microenvironment; neuropathic pain; pancreatic carcinoma; perineural invasion (PNI); prognostic signature

DOI:  https://doi.org/10.3389/fgene.2025.1600883
Research (Wash D C). 2025 ;8 0932

Na+/K+-ATPase Modulates Purinergic P2X3 Receptor Function to Drive Bone Cancer Pain.

Songqiang Huang, Bo Peng, Wanting Dong, Jiapeng He, Hanbin Chen, Jin-Song Bian.

Bone cancer pain (BCP) is one of the most common types of chronic pain in cancer patients, with a prevalence of up to 75%. However, the pathological mechanism and therapeutic approaches are limited. Here, we demonstrated that Na+/K+-ATPase α1 (NKAα1) is a critical regulator of nociception through interaction with purinergic P2X3 receptor (P2X3R) in the dorsal root ganglion (DRG). Conditional knockout of NKAα1 in transient receptor potential vanilloid 1-positive (TRPV1+) neurons led to an increase in P2X3R-dependent Ca2+ influx and neuronal hyperexcitability and also promoted pain hypersensitivity in BCP model mice. In addition, NKAα1 knockout in TRPV1+ neurons further enhanced C-C motif chemokine ligand 5 release, thereby exacerbating spinal glial cell activation and pain hypersensitivity in BCP mice. DR5-12D, a monoclonal antibody to stabilize the expression of NKAα1, markedly inhibited the hyperexcitability of DRG nociceptors and ameliorated pain hypersensitivity in BCP mice. Overall, NKAα1 modulates P2X3R-dependent Ca2+ influx and the excitability of DRG nociceptors, thereby providing valuable theoretical guidance for the treatment of BCP.

DOI: https://doi.org/10.34133/research.0932
J Surg Oncol. 2025 Oct 21.

A Seer-Based Analysis of Survival Predictors in Stage I Colorectal Adenocarcinomas.

Sameh Hany Emile, Nir Horesh, Zoe Garoufalia, Marcus Oosenbrug, Marylise Boutros, Steven D Wexner.

   BACKGROUND: We assessed predictors of overall (OS) and cancer-specific survival (CSS) in stage I colorectal cancer (CRC).
METHODS: Retrospective analysis of patients with stage I colon or rectal adenocarcinomas from the SEER database (2010-2020) Survival was assessed using Kaplan-Meier statistics and multivariable Cox regression analyses. The primary outcomes were 5-year OS and CSS.
RESULTS: 40,001 patients (51.3% male; mean age: 65.1 ± 12.6 years) were included. Colon and rectal cancers accounted for 75.8% and 24.2%, respectively. Five-year OS and CSS were 83.1% (95% CI: 82.6-83.5%) and 93.2% (95% CI: 92.9-93.5%), respectively. Factors independently associated with worse OS were age (HR: 1.07; p < 0.001), male sex (HR:1.48; p < 0.001), Black race (HR: 1.25; p < 0.001), single, divorced, or widowed status (HR: 1.49, 1.46, and 1.43; p < 0.001), tumor size (HR: 1.001; p = 0.008), poorly differentiated carcinomas (HR: 1.32; p < 0.001), undifferentiated carcinomas (HR:1.44; p = 0.026), perineural invasion (HR: 1.84; p < 0.001), elevated CEA levels (HR: 1.68; p < 0.001), and systemic therapy (neoadjuvant: HR: 1.3; p = 0.032, adjuvant: HR: 2.2; p < 0.001, both: HR: 1.97; p < 0.001). Factors independently associated with worse CSS were age (HR: 1.05; p < 0.001), male sex (HR: 1.32; p < 0.001), Black race (HR: 1.43; p < 0.001), marital status (HR: 1.44, 1.28, and 1.68; p < 0.001), tumor size (HR: 1.003; p < 0.001), poorly differentiated carcinomas (HR: 1.77; p < 0.001), perineural invasion (HR: 2.29; p < 0.001), elevated CEA levels (HR: 2.24; p < 0.001), and systemic therapy (neoadjuvant: HR: 2.53; p = 0.032, adjuvant: HR: 4.22; p < 0.001, both: HR: 3.83; p < 0.001).
CONCLUSIONS: Although patients with stage I CRC had excellent survival, single, older, Black, male patients with large, high-grade tumors associated with perineural invasion and elevated CEA levels had a higher mortality risk.

Keywords:  Colorectal Cancer; SEER; prognosis; stage I; survival

DOI:  https://doi.org/10.1002/jso.70111
Int J Surg. 2025 Oct 21.

Schwann cells drive tumor progression through neuro-tumor crosstalk.

Liu Yang, Yu-Xing Zheng, Ji-Peng Liu, Yong-Sheng Xu, Fu-Qi Zhu, Wen-Jun Zhang, Rui Zou.

  Different studies have confirmed the relationship between nerves and tumor cells. Nerve invasion leads to poor prognosis and increased mortality. Neural network in the tumor microenvironment provides the conditions for tumor diffusion and a strong relationship between nerve and tumor interaction, which is also supported by the cellular and molecular mechanisms in the process of nerve growth and nerve repair. Schwann cells (SCs) are the main glial cells of peripheral nerves. They play an important role in the repair of injured nerves, including neuroprotection, neurotrophic, nerve regeneration, nerve regulation and immune regulation, and enhance the microenvironment of nerve injury. These cells form a complex tumor neural microenvironment during the progress of tumors, providing a good basis for tumor invasion and metastasis. SCs can promote the tumor progression (refers to the deterioration of the growth, invasion and metastasis of a malignant tumor, which is manifested by the increase in the volume of the primary tumor, the expansion of the scope of invasion, the appearance of new metastases, and the deterioration of biological behavior) through their phenotype (dedifferentiation). This change in cell phenotype is similar to SCs' response to peripheral nerve injury, revealing the unique biological characteristics of SCs. This article summarizes the biological characteristics of SCs and their functions in the repair of peripheral nerve injury. The possible mechanism of SCs-nerve-tumor crosstalk mode influencing tumor progression was emphatically discussed. Through the SCs level, changing the cell neural network environment to inhibit tumor progression has great prospects and application value.

Keywords:  microenvironment; nerve invasion; schwann cells (sCs); tumor

DOI:  https://doi.org/10.1097/JS9.0000000000003721
Case Rep Neurol Med. 2025 ;2025 6923539

Distinct Imaging Features of Peripheral Nerve Sheath Tumours in NF2-Related Schwannomatosis: A Case Report.

Küpper Hanna, Roggia Cristiana, Winter Natalie, Grimm Alexander, Nägele Thomas, Rosewich Hendrik, Schuhmann Martin Ulrich.

   Introduction: Peripheral nerve sheath tumours (PNST) are an important feature of the NF2-related schwannomatosis. These constitute primarily schwannomas which are characterized as nodular, solitary benign tumours of single fascicles. We here describe a pronounced, extensive, multifascicular enlargement of the right ulnar nerve and bilateral brachial plexus in a teenage patient with NF2-related schwannomatosis. Neither their imaging nor the clinical characterization were consistent with classic schwannomas.
Methods: Within a multimodal work-up, detailed and standardized high-resolution nerve ultrasound was correlated to clinical, electroneurographic, and MRI findings. Follow-up data over 2 years were provided.
Results: The clinical presentation of a slowly progressive, predominantly motor axonal neuropathy of the right ulnar nerve prompted a comprehensive nerve ultrasound examination, initiated by this clinically and neurophysiologically defined "sentinel" finding. Ultrasound imaging revealed an extensive, fusiform enlargement of the right ulnar nerve, as well as bilateral involvement of the brachial plexus, the latter without corresponding clinical symptoms. Subsequent genetic analysis confirmed the diagnosis of NF2-related schwannomatosis.
Discussion: Signs of a mononeuropathy are a frequent manifestation of NF2-related schwannomatosis in childhood. The here presented nerve imaging characteristics, however, did not correspond to classic schwannomas. The fusiform, long-extended, multifascicular enlargement with mixed hyper- and hypoechogenic components on ultrasound, as well as markedly T2-hyperintense and T1-isointense appearance with diffuse gadolinium enhancement on MRI, is consistent with perineurioma. These mesenchymal nerve tumours have rarely been described in NF2-related schwannomatosis. This association is further supported by the present case and highlights the necessity for additional peripheral nerve imaging studies in NF2-related schwannomatosis, including the application of high-resolution ultrasound.

Keywords:  NF2-related schwannomatosis; nerve ultrasound; perineurioma; peripheral nerve sheath tumours (PNST); schwannoma

DOI:  https://doi.org/10.1155/crnm/6923539
J Surg Case Rep. 2025 Oct;2025(10): rjaf820

Schwannoma of the colon presenting as a submucosal lesion: diagnostic challenge and surgical management.

Mohammad Al Yaseen, Ali Toffaha, Hamza A Abdul-Hafez, Mohamed Kurer, Mohamed Abunada, Mahmood Al-Dhaheri.

  Schwannomas are rare benign nerve-sheath tumours that uncommonly involve the gastrointestinal tract, with the colon and rectum among the least frequent sites. We report a 36-year-old man with a 2-year history of central colicky abdominal pain, alternating bowel habits (predominantly constipation), intermittent rectal bleeding and bloating. Computed tomography (CT) and colonoscopy revealed a 2-cm submucosal lesion at 23 cm from the anal verge; endoscopic ultrasound showed a homogeneously hypoechoic, smooth-margined mass originating from the muscularis. The patient underwent laparoscopic anterior resection after endoscopic tattooing. Recovery was uneventful. Histopathology confirmed a 1.5-cm benign colonic schwannoma with clear margins and 17 negative lymph nodes. At follow-up he remained asymptomatic without recurrence. Colorectal schwannoma can mimic gastrointestinal stromal tumour or leiomyoma preoperatively; definitive diagnosis requires histology and immunohistochemistry (S100 positivity), and complete excision with negative margins is curative.

Keywords:  case report; colon; schwannoma; submucosal lesions; surgery

DOI:  https://doi.org/10.1093/jscr/rjaf820