bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2025–10–12
eight papers selected by
Maksym V. Kopanitsa, Charles River Laboratories



  1. J Exp Clin Cancer Res. 2025 Oct 07. 44(1): 281
       BACKGROUND: Cancer-associated fibroblasts (CAFs) are key drivers of neural invasion in pancreatic cancer, yet their regulatory mechanisms remain elusive.This study explores the role of circular RNAs (circRNAs) in CAFs and their involvement in regulating neural invasion in pancreatic cancer.
    METHODS: CAF-derived circRNAs were identified through circRNA high-throughput sequencing and quantitative real-time PCR (qRT-PCR). The impact of CAF-derived circKLHL24 on perineural invasion (PNI) in tumor cells was evaluated both in vitro and in vivo. RNA sequencing, RNA pulldown, RNA immunoprecipitation, and luciferase reporter assays were conducted to identify downstream targets and elucidate the underlying mechanism of circKLHL24 in PNI.
    RESULTS: CircKLHL24 (hsa_circ_0001369), a CAF-specific circRNA, is associated with PNI and poor survival in advanced PDAC. Silencing or overexpressing circKLHL24 in CAFs altered the ability of CAFs to induce tumor cell invasion and nerve infiltration via chemokine (C-X-C Motif) ligand 12 (CXCL12). Mechanistically, first, circKLHL24 binds to the membrane protein Sec31A, inhibiting its ubiquitination and degradation, thereby enhancing CXCL12 secretion. Second, circKLHL24 acts as a sponge for miR-615-5p, relieving its suppression of CXCL12 mRNA and amplifying CXCL12 expression. Moreover, high circKLHL24 levels were positively correlated with elevated serum CXCL12 levels in PDAC and poor patient survival. Targeting circKLHL24 or neutralizing CXCL12 suppresses PDAC invasion and neuronal recruitment in nude mouse and KPC models.
    CONCLUSIONS: The circKLHL24/Sec31A/miR-615-5p/CXCL12 axis is critical for CAF-induced PNI in PDAC. Therefore, circKLHL24 could serve as a potential therapeutic target for PDAC.
    Keywords:  CXCL12; Cancer-associated fibroblasts; Circular RNAs; Perineural invasion
    DOI:  https://doi.org/10.1186/s13046-025-03489-2
  2. Dis Model Mech. 2025 Oct 09. pii: dmm.052471. [Epub ahead of print]
      Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with limited therapeutic options. Here, we present a novel sporadic murine model of Nf1 wild-type MPNST, driven by conditional expression of oncogenic BrafV600E and Pten loss in the glial lineage using the Plp1::CreERT2 driver. This model allows for highly penetrant and rapid tumor induction through spontaneous formation, localized initiation, or cell transplantation. Comparative analysis with Tyr::CreERT2-driven melanoma revealed striking phenotypic divergence despite shared genetic alterations, underscoring the importance of the cell of origin in shaping tumor identity. In this system, MPNST cells show refractory capacities to induce melanocytic trans-differentiation upon melanoma-promoting signaling cues such as canonical Wnt signaling gain of function (GOF) or increased of levels of the epigenetic mark H3K27Me3 upon Ezh2 GOF. Our findings emphasize the significance of lineage context in tumor initiation and provide a foundation for future mechanistic and therapeutic studies.
    Keywords:   Braf ; Pten ; Cancer; MPNST; Mouse model
    DOI:  https://doi.org/10.1242/dmm.052471
  3. Biomed Pharmacother. 2025 Oct 08. pii: S0753-3322(25)00831-5. [Epub ahead of print]192 118637
      Adrenergic signaling in tumors is a very topical issue as catecholamines have been shown to be involved in carcinogenesis, e.g. via chronic stress. The use of adrenergic receptor blockers in monotherapy or in combination therapy for individual tumor types is being investigated by many laboratories. This review summarizes the current knowledge on the role of adrenergic receptors in carcinogenesis and on the possible use of selective/non-selective blockers in the treatment of individual tumor types. In particular, α- and β-blockers have become of interest for repurposing drugs as cancer therapies because they show promising effects against cellular processes leading to cancer initiation and development, not only under in vitro conditions, but also in preclinical and clinical studies. Preclinical studies and the prospect of possible use of these substances in the treatment of certain types of tumors complete the current state of the issue.
    Keywords:  Adrenergic receptors; Alpha-blockers; Beta-blockers; Cancer; Stress
    DOI:  https://doi.org/10.1016/j.biopha.2025.118637
  4. J Exp Clin Cancer Res. 2025 Oct 06. 44(1): 280
       BACKGROUND: Peripheral nerve damage is intricately linked to the progression of various solid tumors. However, its effect on antitumor immunity and precise underlying mechanisms remain poorly understood. This study aimed to elucidate the effect of peripheral nerve damage and its subsequent immune-modulating effects influence on breast cancer progression.
    METHODS: We analyzed nerve injury markers in the TCGA-BRCA database and clinical samples. In vivo experiments were conducted using orthotopic breast cancer models with chemical sympathetic denervation (6-OHDA) or nerve lysate/neurofilament light chain (NFL) treatment, where NFL was identified as a key effector molecule through mass spectrometry screening. The tumor microenvironment was evaluated by flow cytometry, multiplex immunohistochemistry, and single-cell RNA sequencing. In vitro co-culture systems were established to investigate the effects of NFL on macrophages and CD8+ T cells, with transcriptomic profiling revealing that NFL-activated macrophage supernatants induced CD8+ T cell senescence via NF-κB signal pathway activation.
    RESULTS: Peripheral nerve injury was associated with poor prognosis and immune evasion in breast cancer patients. In mouse models, chemical sympathectomy (6-OHDA) and nerve lysates injection both accelerated tumor growth, suggesting that nerve damage promotes immune escape. Single-cell RNA sequencing (scRNA-seq) further revealed that nerve injury increased tumor-associated macrophages (TAMs) proportion by promoting TAMs proliferation and attracting macrophages. The key effector molecule of nerve lysates neurofilament light chain (NFL) was identified with the TAMs proliferation effect, and intratumoral NFL administration recapitulated the pro-tumor effects of nerve damage and perfomed the same immune-modulating effects as 6-OHDA and nerve lysates. Importantly, NFL-induced TAM enrichment and remodeling promoted CD8+ T cell senescence, as evidenced by transcriptomic analysis showing NF-κB pathway activation and verified with NF-κB inhibitor (BAY 11-7082) in vitro, resulting in breast cancer immune escape.
    CONCLUSION: These findings underscore the critical role of peripheral nerve injury in reshaping the interplay between TAMs and antitumor immunity, via NFL-driven NF-κB activation and T cell dysfunction. Suggesting that neuroprotection could serve as a promising strategy to restore anticancer immunosurveillance.
    Keywords:  A nerve damage biomarker; NFL; Reprograms TAMs to induce CD8+T cell senescence; Revealing a novel neuro-immune axis in breast cancer
    DOI:  https://doi.org/10.1186/s13046-025-03545-x
  5. Int Immunopharmacol. 2025 Oct 06. pii: S1567-5769(25)01636-4. [Epub ahead of print]166 115645
      As a core AP-1 transcription factor, FOS like-1 (FOSL1) drives cell proliferation, differentiation, transformation, and tumorigenesis by regulating downstream targets via heterodimer formation. Pan-cancer analyses confirm its characteristic overexpression in solid tumors, with expression levels strongly correlating with tumor invasiveness and metastasis. Emerging evidence highlights tumor-nerve crosstalk in the tumor microenvironment (TME) as a key driver of progression, and recent studies identify FOSL1 as a central regulatory hub linking tumors and the nervous system. It modulates tumor-neural interactions through mechanisms that include Schwann cell reprogramming, chemokine network construction, axon orientation regulation, synaptic connection modulation, and immune-neuro-tumor synergy, thereby promoting neural remodeling, invasion, metastasis, and TME reprogramming. Elucidating FOSL1's multidimensional regulation of tumor-nerve crosstalk not only offers new insights into tumor neural dependency but also establishes a theoretical basis for developing FOSL1-based diagnostic markers, prognostic tools, and novel targeted therapies, with substantial clinical translational potential.
    Keywords:  FOSL1; Peripheral nerve invasion; Tumor microenvironment; Tumor-neural interaction; Tumorigenesis
    DOI:  https://doi.org/10.1016/j.intimp.2025.115645
  6. Med Sci Monit. 2025 Oct 10. 31 e951110
      BACKGROUND Perineural invasion (PNI) is strongly associated with poor clinical outcomes in colorectal cancer (CRC). However, no machine learning diagnostic model based on pathomics has been established for PNI detection in CRC. To address this issue, we sought to construct a predictive model for PNI grounded in pathological features to enhance diagnostic efficiency. MATERIAL AND METHODS We analyzed hematoxylin and eosin-stained histopathological slides from the CRC tissues retrospectively. Segmentation of the acquired images was conducted via CellProfiler, an automated pipeline supporting the extraction of morphological features. To optimize feature selection, we applied the LASSO algorithm, followed by multiple machine learning models to develop diagnostic classifiers for PNI. Furthermore, we investigated the clinicopathological significance of PNI, including its association with T stage, lymph node metastasis, lymphovascular invasion, and molecular biomarkers. RESULTS We used 430 CRC surgical resection slides for training, testing, and external validation. A total of 615 histopathological features were extracted, and 10 of them were screened by LASSO to construct diagnostic models for PNI. The models demonstrated robust predictive performance across all cohorts. LightGBM achieved the highest diagnostic accuracy, yielding AUCs of 0.996 (95% CI: 0.991-1.000, training), 0.935 (95% CI: 0.888-0.978, testing), and 0.918 (95% CI: 0.861-0.967, external validation). Patients with CRC with PNI exhibited higher T stage, increased lymph node metastasis, and more frequent lymphovascular invasion. CONCLUSIONS The LightGBM model, based on histopathological features, can improve the diagnostic efficiency of PNI. CRC with PNI is associated with poor prognosis.
    DOI:  https://doi.org/10.12659/MSM.951110
  7. Exp Oncol. 2025 Oct 07. 47(2): 127-142
      Chronic stress is one of the key exogenous factors that can significantly affect tumor cell biology by disrupting the regulation of the tumor microenvironment (TME), thereby promoting the manifestation of the malignant process. Activation of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system induced by stressors leads to the secretion of glucocorticoids and catecholamines, which contribute to the deregulation of microenvironmental components that determine the aggressiveness of malignant neoplasms. This review systematizes the current views on the impact of stress-induced signals on the immune, stromal, vascular, and metabolic components of the TME and analyzes their contribution to the formation of an aggressive tumor phenotype. Particular attention is given to the interplay between neurohumoral stress, the gut, and the intratumoral microbiome, forming a complex networked environment supporting tumor progression. Advancing the understanding of molecular interactions between stress mediators and cellular elements of the TME will provide a foundation for developing innovative therapeutic strategies targeting not only the tumor itself but also minimizing the adverse effects of stress on individual components of the TME.
    DOI:  https://doi.org/10.15407/exp-oncology.2025.02.127
  8. Neurophysiol Clin. 2025 Oct 03. pii: S0987-7053(25)00068-1. [Epub ahead of print]55(6): 103110
       OBJECTIVES: Non-invasive brain stimulation techniques-particularly repetitive transcranial magnetic stimulation (rTMS) have emerged as promising alternatives to traditional pharmacological treatments for pain management in non-central nervous system cancer patients. By modulating neural circuits involved in pain processing through mechanisms of neuroplasticity, these interventions may also improve cognitive functioning, psychological aspects, and quality of life (QoL). The present systematic review aims to investigate the use of rTMS for cancer-related pain and psychological aspects.
    METHODS: A comprehensive search was conducted in three electronic scientific databases-PubMed, Scopus, and Embase. Six studies were identified and included, comprising pilot studies, randomized controlled trials, and one randomized clinical trial. PRISMA 2020 guidelines for systematic review were followed.
    RESULTS: All these studies investigated the use of rTMS to manage pain and psychological aspects such as QoL in patients with different types of oncological conditions, including breast, non-small cell lung, and gynecological cancer, multiple myeloma, and cell glioma. The results suggest a multidimensional improvement in QoL, well-being, and emotional dimension. Notably, a significant reduction in pain intensity was observed following rTMS treatment across all studies.
    CONCLUSION: Although limited in number, current studies suggest that rTMS is a promising non-pharmacological intervention for managing cancer-related pain and enhancing psychological well-being. Further high-quality trials are needed to confirm these findings and establish standardized treatment protocols.
    Keywords:  Cancer-related pain; Non-invasive brain stimulation; Psychological aspects; Quality of life; Repetitive transcranial magnetic stimulation (rTMS)
    DOI:  https://doi.org/10.1016/j.neucli.2025.103110