bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2025–08–31
eight papers selected by
Maksym V. Kopanitsa, Charles River Laboratories



  1. Ann Surg. 2025 Aug 26.
       OBJECTIVE: This study aims to prospectively validate a perineural invasion (PNI) severity score in predicting recurrence and survival in resected PDAC.
    BACKGROUND: PNI in pancreatic ductal adenocarcinoma (PDAC) is characterized by clinical and morphologic heterogeneity. Although a specific score for PNI severity has been proposed, it lacks validation.
    METHODS: In this prospective registered (NCT04024358) monocentric study, 300 patients undergoing pancreatectomy between March 2019 and February 2022 were analyzed. PNI was scored as: 0 absent; 1 presence of neoplasia along nerves<3 mm; 2 neoplastic infiltration of nerves≥3 mm and/or massive PNI and/or necrosis of the infiltrated nerves. Association of PNI with disease recurrence and survival was evaluated.
    RESULTS: Of 300 patients, 86% presented PNI, with 148 (49.3%) having PNI 1 and 110 (36.7%) PNI 2. Neoadjuvant treatment did not influence PNI (89.7% vs. 83.9% after treatment, P=0.332). PNI severity significantly correlated with worsening pathological features, shorter disease recurrence (24 mo for PNI 0, 17 for PNI 1 and 15 for PNI 2, P<0.01) and survival (57 mo for PNI 0, 51 for PNI 1 and 32 for PNI 2, P<0.01). PNI 2 independently predicted both recurrence and survival with HR of 2.082 (P=0.006) and 3.304 (P=0.014). PNI 2 benefitted most from adjuvant treatment, with longer disease recurrence time (17 vs. 12 mo; P=0.007) and survival (36 vs. 17 mo; P=0.004).
    CONCLUSIONS: The PNI severity score improves prognostic stratification of resected PDAC and identifies patients who benefit the most from adjuvant treatment.
    Keywords:  Perineural invasion; pancreatic cancer; prognostic score
    DOI:  https://doi.org/10.1097/SLA.0000000000006920
  2. BMC Cancer. 2025 Aug 23. 25(1): 1367
       BACKGROUND: To explore the efficacy of a deep learning (DL) model in predicting perineural invasion (PNI) in prostate cancer (PCa) by conducting multiparametric MRI (mpMRI)-based tumor heterogeneity analysis.
    METHODS: This retrospective study included 397 patients with PCa from two medical centers. The patients were divided into training, internal validation (in-vad), and independent external validation (ex-vad) cohorts (n = 173, 74, and 150, respectively). mpMRI-based habitat analysis, comprising T2-weighted imaging, diffusion-weighted imaging, and apparent diffusion coefficient sequences, was performed followed by DL, deep feature selection, and filtration to compute a radscore. Subsequently, six models were constructed: one clinical model, four habitat models (habitats 1, 2, 3, and whole-tumor), and one combined model. Receiver operating characteristic curve analysis was performed to evaluate the models' ability to predict PNI.
    RESULTS: The four habitat models exhibited robust performance in predicting PNI, with area under the curve (AUC) values of 0.862-0.935, 0.802-0.957, and 0.859-0.939 in the training, in-vad, and ex-vad cohorts, respectively. The clinical model had AUC values of 0.832, 0.818, and 0.789 in the training, in-vad, and ex-vad cohorts, respectively. The combined model outperformed the clinical and habitat models, with AUC, sensitivity, and specificity values of 0.999, 1, and 0.955 for the training cohort. Decision curve analysis and clinical impact curve analysis indicated favorable clinical applicability and utility of the combined model.
    CONCLUSION: DL models constructed through mpMRI-based habitat analysis accurately predict the PNI status of PCa.
    Keywords:  Deep learning; Habitat analysis; Magnetic resonance imaging; Perineural invasion; Prostate cancer
    DOI:  https://doi.org/10.1186/s12885-025-14759-9
  3. Nat Cancer. 2025 Aug 21.
      The bidirectional interaction between the brain and peripheral tumors is critical but poorly understood. Here we show GABAergic neurons in the lateral septum, a key brain region implicated in emotional regulation, connect via a polysynaptic circuit to enteric cholinergic neurons that send nerve fibers into the tumor microenvironment, which were then hijacked by colorectal cancer cells to sustain tumor growth in mice. Functionally, activation of this septo-enteric circuit induces GABA release from enteric cholinergic neurons, which in turn activates epsilon-subunit-containing GABAA receptors on tumor cells. Notably, chronic restraint stress potentiates activity within this circuit, exacerbating tumor progression. Clinically, patients with colorectal cancer exhibiting elevated neuronal activity in the septal region present with larger primary tumors. Collectively, our findings uncover a stress-sensitive septo-enteric polysynaptic pathway exploited by cancer cells to promote tumor growth, underscoring the previously unrecognized role of lateral septum-mediated neural circuitry and psychological stress in cancer progression.
    DOI:  https://doi.org/10.1038/s43018-025-01033-x
  4. Nature. 2025 Aug 20.
      Perineural invasion (PNI) is a well-established factor of poor prognosis in multiple cancer types1, yet its mechanism remains unclear. Here we provide clinical and mechanistic insights into the role of PNI and cancer-induced nerve injury (CINI) in resistance to anti-PD-1 therapy. Our study demonstrates that PNI and CINI of tumour-associated nerves are associated with poor response to anti-PD-1 therapy among patients with cutaneous squamous cell carcinoma, melanoma and gastric cancer. Electron microscopy and electrical conduction analyses reveal that cancer cells degrade the nerve fibre myelin sheets. The injured neurons respond by autonomously initiating IL-6- and type I interferon-mediated inflammation to promote nerve healing and regeneration. As the tumour grows, the CINI burden increases, and its associated inflammation becomes chronic and skews the general immune tone within the tumour microenvironment into a suppressive and exhaustive state. The CINI-driven anti-PD-1 resistance can be reversed by targeting multiple steps in the CINI signalling process: denervating the tumour, conditional knockout of the transcription factor mediating the injury signal within neurons (Atf3), knockout of interferon-α receptor signalling (Ifnar1-/-) or by combining anti-PD-1 and anti-IL-6-receptor blockade. Our findings demonstrate the direct immunoregulatory roles of CINI and its therapeutic potential.
    DOI:  https://doi.org/10.1038/s41586-025-09370-8
  5. Biomedicines. 2025 Jul 22. pii: 1789. [Epub ahead of print]13(8):
      Background: Prostate cancer is a common malignancy among men worldwide, with various histopathologic features that influence its progression and prognosis. One such feature is perineural invasion (PNI), which has been associated with aggressive disease. In this retrospective study, we analyzed genomic alterations associated with PNI in patients who underwent radical prostatectomy. Methods: A total of 421 prostate cancer patients who underwent radical prostatectomy without neoadjuvant therapy were identified from The Cancer Genome Atlas. PNI was present in 378 patients (89.8%) and absent in 43 (10.2%). Differentially expressed genes were identified, and mRNA expression levels of key genes were analyzed. The prognostic significance of these genes was evaluated using log-rank tests and Cox proportional hazards models to estimate hazard ratios and 95% confidence intervals. Results: Levels of COL9A3, ASPN, ESR1, MUC1, PIP, SFRP4, KRT19, CLDN1, and COMP were significantly higher in the tumor tissues of patients in the PNI group compared to those in the non-PNI group (q < 0.05), and RYR2, MME, and AZGP1 expression levels were significantly higher in the non-PNI group (q < 0.05). A high mRNA expression level of AZGP1 was associated with longer disease-free survival, whereas high mRNA expressions of ASPN, COMP, RYR2, and SFRP4 were associated with shorter disease-free survival. Conclusions: Prostate cancer patients with genomic alterations associated with PNI may face a higher risk of disease progression after prostatectomy, highlighting the need for further prospective studies to validate these findings.
    Keywords:  perineural invasion; prognostic biomarkers; prostate cancer
    DOI:  https://doi.org/10.3390/biomedicines13081789
  6. Front Immunol. 2025 ;16 1635331
       Background: Emerging evidence suggests that beta-blockers (BBs) may influence cancer progression by modulating the neuroimmune axis. However, clinical findings remain heterogeneous, necessitating a comprehensive evaluation of their impact on survival outcomes and immune modulation across malignancies.
    Methods: We conducted a systematic review and meta-analysis following PRISMA guidelines, analyzing 79 studies from PubMed, Embase, and Web of Science. Pooled hazard ratios (HRs) for overall survival (OS) and cancer-specific survival (CSS) were calculated using random-effects models. Subgroup analyses explored effects by cancer type, BB class (non-selective vs. β1-selective), and concurrent immunotherapy. Immune biomarkers (e.g., PD-L1 expression, tumor-infiltrating lymphocytes) were qualitatively synthesized.
    Results: BB use showed no significant overall effect on CSS (HR = 0.97, 95% CI: 0.92-1.02) but exhibited substantial heterogeneity (I² = 80%). Protective associations were observed in breast cancer (HR = 0.27-0.50) and melanoma, while detrimental effects emerged in pancreatic and head/neck cancers (HR > 1.0). Clinically, BBs combined with immune checkpoint inhibitors (ICIs) improved survival (HR=0.91, 95% CI: 0.85-0.98), particularly in PD-L1+ tumors (OR=1.29 for enhanced expression). Non-selective BBs showed stronger immune modulation (CD8+ T-cell SMD=0.49 vs 0.22 for β1-selective).
    Conclusion: BBs demonstrate clinically meaningful benefits when combined with immunotherapy (HR=0.91) particularly in β2-AR+ melanoma and breast cancer, but show potential harm in pancreatic/head-neck cancers (HR>1.0). These results support preferential use of propranolol (20-40mg/day) in immunotherapy-treated melanoma, and avoidance of routine BB use in non-immunogenic tumors without adrenergic profiling. Prospective trials should validate these selection criteria.
    Keywords:  Beta-blockers; cancer neuroimmunology; immune checkpoint inhibitors; meta-analysis; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1635331
  7. Front Neuroendocrinol. 2025 Aug 23. pii: S0091-3022(25)00042-1. [Epub ahead of print]79 101216
      The diffuse neuroendocrine system (DNES) consists of dispersed neuroendocrine (NE) cells that bridge nervous, immune, and endocrine pathways across organs. Evolutionarily, DNES traces to primitive metazoans where single cells combined neural and immune roles, later diversifying into specialized vertebrate NE cells. Hallmark traits include dense-core granules, amine metabolism, "salt-and-pepper" chromatin, and regulation by ASCL1, NEUROG3, and INSM1. Remarkable plasticity allows immune and epithelial cells to acquire NE features under stress, while carcinomas exploit this program to form aggressive neuroendocrine tumors (NETs) and resist therapy. Canonical neuroimmune circuits, the Vagus-driven inflammatory reflex and hypothalamic-pituitary-adrenal stress axis, illustrate DNES coordination of systemic responses. Clinically, DNES-derived neoplasms span multiple organs, produce diverse hormonal syndromes, and are managed with somatostatin analogues, epigenetic drugs, and emerging immunotherapies. Recognizing DNES as a diffuse, integrative regulatory network clarifies mechanisms of chronic inflammation and cancer evolution and offers novel therapeutic entry points for disorders ranging from asthma to pancreatic neuroendocrine carcinomas.
    Keywords:  Cellular plasticity; Diffuse neuroendocrine system; Homeostasis; Neuroendocrine cells; Neuroendocrine tumors; Neuroimmune interactions
    DOI:  https://doi.org/10.1016/j.yfrne.2025.101216
  8. Front Oncol. 2025 ;15 1644895
      As the most frequent and aggressive subtype of ovarian cancer, high-grade serous ovarian cancer (HGSOC) often advances unnoticed due to its subtle early symptoms, which in turn leads to a significantly low five-year survival rate. The process of immune evasion, often achieved by constructing an immunosuppressive microenvironment through various pathways, stands as a critical feature of tumor biology. At the same time, emerging studies reveal a strong association between the sympathetic nervous system (SNS) and immune regulation in the tumor microenvironment (TME). In HGSOC, SNS activation releases neurotransmitters like norepinephrine, which affect immune cells, suppress their functions, weaken anti-tumor responses, and promote the recruitment and activation of immunosuppressive cells. By recruiting immune-suppressive cells, altering the extracellular matrix to construct physical barriers, and increasing pro-angiogenic signals, the SNS reshapes the tumor microenvironment in a way that hampers immunotherapy. Clinically, higher levels of SNS activation are linked to worse outcomes and therapeutic resistance in HGSOC. Additionally, preclinical studies demonstrate that targeting the SNS using β-adrenergic receptor inhibitors can improve immune activation and enhance treatment responses. Moving forward, research needs to further examine SNS mechanisms to support the development of advanced therapeutic strategies.
    Keywords:  high-grade serous ovarian cancer; immune evasion; immunotherapy; sympathetic nervous system; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2025.1644895