bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2025–12–14
ten papers selected by
Maksym V. Kopanitsa, Charles River Laboratories
  1. Key developments in the cancer neuroscience field.
  2. Advances in the study of the relationship between neurotransmitters and gastric cancer.
  3. Lactylation-driven NSUN2-mediated RNA m5C modification promotes perineural invasion in pancreatic cancer.
  4. Comprehensive Multi-Omic Characterization of Perineural Invasion in Cervical Cancer Reveals Diagnostic Markers, Molecular Drivers, and Therapeutic Strategies.
  5. Pancreatic cancer is evasive. Is the nervous system the reason why?
  6. Deep learning to predict extrapancreatic perineural invasion at CT images.
  7. Surgical management of a giant retrorectal ganglioneuroma via an open anterior approach: a case report.
  8. Tumor-associated astrocytes inhibit tumor cell apoptosis through TNF-α-TNF receptor 2-NF-κB pathway in lung cancer brain metastasis.
  9. Baseline neuronal antibodies in patients with small cell lung cancer are not necessarily associated with post-immune checkpoint inhibitors neurotoxicities.
  10. The impact of primary tumor location of colorectal cancer on the survival outcome of patients with brain metastasis: a systematic review and meta-analysis.
  1. Nat Cancer. 2025 Dec 10.
    Key developments in the cancer neuroscience field.
    Michelle Monje, Frank Winkler.
      
    DOI:  https://doi.org/10.1038/s43018-025-01082-2
  2. World J Gastroenterol. 2025 Nov 28. 31(44): 113793
    Advances in the study of the relationship between neurotransmitters and gastric cancer.
    You-Zhao Liu, Wen-Xuan Liu, Wen-Hong Deng.
      Emerging evidence underscores the critical, yet frequently underrecognized, role of the nervous system in the development and progression of gastric cancer (GC), primarily mediated through complex neuro-tumoral interactions and modulation of immune responses. GC cells actively invade neural structures, inducing aberrant nerve growth, while, in parallel, neural components infiltrate the tumor microenvironment, collectively promoting tumor proliferation, dissemination, and resistance to therapy. These bidirectional processes are regulated by diverse neurotransmitter systems-including monoaminergic, cholinergic, amino acid-based, peptidergic, and purinergic pathways-which are aberrantly produced by both neurons and malignant cells. Beyond their canonical function in neural signaling, these neuromediators exert diverse effects on tumor biology, coordinating multiple facets of GC progression, including invasion, metastasis, and cellular expansion. This review synthesizes current advances and outlines future directions in elucidating the mechanistic contributions of neurotransmitters to GC pathophysiology.
    Keywords:  Gastric cancer; Neuro-immune regulation; Neurotransmitters; Signaling pathway transmission; Tumor microenvironment
    DOI:  https://doi.org/10.3748/wjg.v31.i44.113793
  3. Theranostics. 2026 ;16(4): 1782-1803
    Lactylation-driven NSUN2-mediated RNA m5C modification promotes perineural invasion in pancreatic cancer.
    Tianhao Huang, Chonghui Hu, Huimou Chen, Honghui Jiang, Tingting Li, Qing Tian, Rihua He, Yuan Yuan, Yong Jiang, Yu Zhou, Qing Lin, Zhihua Li, Mingming Xiao, Xuebiao Wei, Rufu Chen, Shangyou Zheng.
      Background: Perineural invasion (PNI) is a key biological feature underpinning the high malignancy and poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Lysine lactylation (Kla), a metabolite-stress-induced post-translational modification, plays crucial regulatory roles in diverse biological processes. The RNA methyltransferase NSUN2 is essential for cancer invasion and metastasis. However, the mechanisms by which NSUN2 contributes to lactylation-driven PNI in PDAC remain to be elucidated. Methods: We assessed tumor lactate / pan-lactylation, NSUN2 lactylation, and PNI in human PDAC cohorts with survival follow-up. Functional studies used PDAC cell lines for migration/invasion assays, dorsal-root-ganglion (DRG) co-culture, and neurite-outgrowth assays under lactate or enzymatic perturbations. Mechanistic interrogation combined NSUN2 knockout, CRISPR knock-in mutants at K692 (K692R/E), co-immunoprecipitation, RIP-seq, MeRIP-qPCR, and actinomycin-D chase to test mRNA binding, m5C modification, and stability of CDCP1/STC1. In vivo validation employed a sciatic nerve invasion model and a KPC genetically engineered mouse model to assess tumor-nerve infiltration and disease progression. Results: Lactylated NSUN2 is markedly upregulated in mice and human PDAC with more severe PNI, and is significantly associated with poorer prognosis. Functionally, inhibiting lactylation or blocking NSUN2 markedly attenuated tumor-nerve interactions and neural invasion. Mechanistically, lactate accumulation leads to the lactylation of NSUN2 at lysine 692 (K692), subsequently inhibiting its ubiquitination and degradation. lactylation of NSUN2 mediated m5C modification on CDCP1 and STC1 mRNA, enhanced their mRNA stability. Conclusions: This study identifies lactate-driven NSUN2 K692 lactylation as a key driver of perineural invasion in PDAC. We define a lactate-NSUN2-m5C-CDCP1/STC1 axis that links metabolic stress-induced lysine lactylation to mRNA methylation-dependent stabilization of pro-invasive transcripts, highlighting actionable therapeutic targets to restrain neural invasion and improve patient outcomes.
    Keywords:  NSUN2; lactylation modification; m5C; pancreatic ductal adenocarcinoma (PDAC); perineural invasion
    DOI:  https://doi.org/10.7150/thno.122294
  4. Cancer Res. 2025 Dec 11.
    Comprehensive Multi-Omic Characterization of Perineural Invasion in Cervical Cancer Reveals Diagnostic Markers, Molecular Drivers, and Therapeutic Strategies.
    Ting Wan, Ting Deng, Xinxin Peng, Guangyao Cai, He Huang, Yihong Ling, Shangbing Gao, Hongyue Li, Danyang Yu, Haonan Li, Yining Zhao, Han Liang, Jihong Liu.
      Perineural invasion (PNI) is an important pathological feature of cervical cancer that is associated with poor prognosis and provides key information for clinical decisions. A better understanding of the molecular mechanisms underlying PNI could lead to improved patient treatment strategies. Here, we generated whole-exome, whole-genome, and RNA-sequencing data from tumors and matched normal clinical samples of 45 cervical cancer patients and performed a comparative analysis between 23 PNI and 22 non-PNI tumors. A robust machine learning approach identified a three-gene expression signature of MT1G, NPAS1, and SPRY1 that could predict the tumor PNI status with high accuracy, which was validated using an independent cohort (18 PNI and 19 non-PNI). Loss-of-function FBXW7 mutations were identified as driver events for PNI that lead to increased MYC activity and an immunosuppressive tumor microenvironment. Finally, a deep-learning model for predicting the drug efficacy over patients' transcriptomic data revealed OTX015, a BET inhibitor, as a promising treatment that targets mutated FBXW7 PNI tumors. This study provides a rich resource for elucidating the molecular mechanisms of PNI tumors, laying a critical foundation for developing effective diagnostic and therapeutic strategies for PNI tumors in cervical cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-0149
  5. Nature. 2025 Dec;648(8093): S49-S50
    Pancreatic cancer is evasive. Is the nervous system the reason why?
    Laura Dattaro.
      
    Keywords:  Cancer; Drug discovery; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-03943-3
  6. Ann Med. 2025 Dec;57(1): 2568116
    Deep learning to predict extrapancreatic perineural invasion at CT images.
    Zhenghua Cai, Liwen Zou, Qi Li, Jun Chen, Yudong Qiu, Jingjing Ji, Liang Mao.
       BACKGROUND: Extrapancreatic perineural invasion (EPNI) was an adverse prognostic factor in patients with pancreatic ductal adenocarcinoma (PDAC) and responsible for positive resection margin. This study aimed to develop an automatic model for segmenting the extrapancreatic nerve plexus and diagnosing EPNI.
    METHODS: In this retrospective study, patients diagnosed with PDAC who underwent enhanced computer tomography scans between August 2018 and December 2022 were enrolled. These cases were divided into training sets with radiological EPNI labels, and validation sets with pathological EPNI labels. The extrapancreatic nerve plexus was segmented first via the nnUNet network and attention mechanism under the background of segmentation of PDAC and adjacent vessels. A 2D classifier was applied to diagnose EPNI based on the segmentation of the nerve plexus. The Dice similarity coefficients (DSCs), receiver operating characteristic (ROC) curve, and diagnostic accuracy were employed to evaluate the performance of the model.
    RESULTS: A total of 332 consecutive patients were enrolled and classified into the training (n = 282) and validation (n = 50) sets. Patients diagnosed with EPNI accounted for 177 of the 332 patients (53.3%). On the one hand, the model showed modest DSCs in segmenting nerve plexus around celiac axis (CA), superior mesenteric artery (SMA), and common hepatic artery (CHA), which were 60, 68.2 and 35.7%, respectively. On the other hand, the model had a favorable performance in diagnosing EPNI; the accuracy and areas under the ROC curve were 0.797, 0.8 in training set and 0.72, 0.85 in the validation set.
    CONCLUSIONS: The fully automatic deep learning model for segmenting the nerve plexus and diagnosing EPNI was a novel and promising tool. Further studies are required to improve the model performance.
    Keywords:  Pancreatic ductal adenocarcinoma; deep learning model; extrapancreatic nerve plexus; extrapancreatic perineural invasion; segmentation
    DOI:  https://doi.org/10.1080/07853890.2025.2568116
  7. Ann Med Surg (Lond). 2025 Dec;87(12): 9035-9038
    Surgical management of a giant retrorectal ganglioneuroma via an open anterior approach: a case report.
    Elahe Radmehr, Mehdi Zeinalizadeh, Faeze Salahshour, Ali Hadipour, Seyed Mohsen Ahmadi Tafti.
       Introduction and importance: Retrorectal ganglioneuromas (GNs) are exceptionally rare, benign tumors originating from neural crest cells of the sympathetic nervous system. Their presacral location presents significant surgical challenges.
    Case presentation: This case report describes the successful open anterior resection of a giant retrorectal GN measuring 10.5 cm in craniocaudal length in a 50-year-old man presenting with chronic pelvic pain and dyschezia.
    Clinical discussion: Preoperative magnetic resonance imaging suggested a retrorectal schwannoma as the most likely diagnosis, while postoperative pathology revealed the mass to be a GN, highlighting the difficulty in differentiating retrorectal neurogenic tumors based on imaging alone. The extensive adherence of the tumor to the sacrum and left internal iliac artery necessitated ligation of the artery and a piecemeal resection technique, requiring a multidisciplinary team involving colorectal, neurosurgical, and vascular surgery.
    Conclusion: Despite a successful outcome with transient postoperative claudication, this case underscores the surgical complexities of large GNs and emphasizes the need for further research into less invasive surgical approaches to minimize complications.
    Keywords:  case report; giant retrorectal ganglioneuroma; neurogenic tumor; pelvic pain; preoperative misdiagnosis
    DOI:  https://doi.org/10.1097/MS9.0000000000004271
  8. Carcinogenesis. 2025 Dec 13. pii: bgaf090. [Epub ahead of print]
    Tumor-associated astrocytes inhibit tumor cell apoptosis through TNF-α-TNF receptor 2-NF-κB pathway in lung cancer brain metastasis.
    Shuo Zhang, Jinjin Cai, Yingying Feng, Man Yang, Yuhang Li, Yanghui Qu, Li Zhang, Chaonan Zheng, Yuan Wang.
      Lung cancer represents the leading cause of cancer-related mortality worldwide, with up to 50% of cases developing brain metastasis during disease progression. Current therapeutic options for brain metastasis remain limited, resulting in poor clinical outcomes. Previous studies have demonstrated that tumor cell invasion into the brain involves localized activation of astrocytes, with these tumor-associated astrocytes (TAAs) exhibiting either pro-tumor or anti-tumor effects. However, the role of astrocytes during post-colonization stages remains unclear. In this study, employing both a murine model of lung cancer brain metastasis and an in vitro co-culture system, we identified the presence of astrocytes within the tumor microenvironment of both clinical specimens and experimental models. Our in vitro experiments revealed that astrocytes significantly enhanced tumor cell survival without affecting proliferation, primarily through inhibition of apoptosis. Mechanistic investigations demonstrated that astrocyte-derived TNF-α mediates this anti-apoptotic effect via activation of the NF-κB signaling pathway in tumor cells. Genetic knockdown of TNF receptor 2 (TNFR2) in tumor cells or pharmacological inhibition of the NF-κB pathway effectively abolished this protective effect. Importantly, TNFR2 knockdown increased intracranial tumabstor cell apoptosis and prolonged survival in the brain metastasis mouse model. These findings collectively demonstrate that TAAs in lung cancer brain metastasis promote tumor cell survival through a TNFR2-NF-κB-dependent mechanism mediated by TNF-α secretion.
    Keywords:  Apoptosis; Astrocyte; Lung cancer brain metastasis; NF-κB signaling pathway; TNF-α
    DOI:  https://doi.org/10.1093/carcin/bgaf090
  9. Front Immunol. 2025 ;16 1681765
    Baseline neuronal antibodies in patients with small cell lung cancer are not necessarily associated with post-immune checkpoint inhibitors neurotoxicities.
    Simone Rossi, Elisa Andrini, Rita Rinaldi, Tania Silvestri, Maria Giovanna Formelli, Adriana Di Odoardo, Barbara Lenzi, Maria Guarino, Davide Campana, Giuseppe Lamberti.
       Background and objectives: Autoantibodies against intracellular neuronal antigens (IC-Abs) can be found in neurologically asymptomatic patients with small cell lung cancer (SCLC) and have been proposed as a predictive biomarker for the development of post-immune checkpoint inhibitors (ICIs) neurotoxicities. The aim of this study was to prospectively evaluate the association of baseline neural antibodies with immune-related adverse events (irAEs) - including neurological irAEs (n-irAEs) - and oncological outcomes in patients with SCLC following ICI therapy.
    Methods: In this prospective cohort study, consecutive patients with SCLC eligible for treatment with ICI were assessed for the presence of IC-Abs with both indirect immunofluorescence (IIF) tissue-based assay (TBA) and line-blot and underwent baseline neurological evaluation prior to ICI initiation. Patients were longitudinally monitored for irAEs occurrence and oncological outcomes. Comparisons between groups, time-to-event and multivariable analyses were performed.
    Results: Fifty-six neurologically asymptomatic patients with SCLC (median age 70.5 years, 38% female) were included. Nineteen (34%) had IC-Abs prior to ICI-treatment (anti-Hu, n=7 [37%]; anti-Zic4, n=6 [32%]; anti-SOX1, n=3 [16%]; anti-SOX1 and anti-Zic4, n=2 [11%]; anti-Purkinje cerebellar cells, n=1 [5%]). Following ICI-treatment, two patients (3.6%) developed a n-irAE (one with baseline anti-Hu antibodies; one without baseline IC-Abs). The presence of baseline IC-Abs was not associated with an increased incidence of n-irAEs. However, anti-Hu antibody positivity was associated with an increased risk of irAEs of any type (OR 8.3; 95% CI, 1.22-56.54). A non-significant trend toward longer progression-free survival was observed in anti-Hu-positive patients (9.4 vs 5.7 months; p=0.10).
    Discussion: The presence of baseline IC-Abs may not be associated with the occurrence of post-ICI neurotoxicities in patients with SCLC. However, anti-Hu antibody positivity correlates with an increased risk of irAEs of any type. Larger studies are needed to assess the safety of ICI therapy in patients with SCLC harbouring neural antibodies and to investigate their potential role as predictive biomarkers of post-ICI neurotoxicities.
    Keywords:  immune checkpoint inhibitor; immunotherapy; neurotoxicity; paraneoplastic neurologic syndrome; small cell lung cancer (SCLC)
    DOI:  https://doi.org/10.3389/fimmu.2025.1681765
  10. Eur J Med Res. 2025 Dec 10.
    The impact of primary tumor location of colorectal cancer on the survival outcome of patients with brain metastasis: a systematic review and meta-analysis.
    Tsung-Chiao Tsai, Hany Atwan, Chaeseong Yim, Junmin Song, Roha Saeed Memon, Muhammad Fahimuddin, Changlin Gong, Yu Chang, Abhishek Kumar.
       OBJECTIVES: Several prior studies have shown that in metastasized colorectal cancer, the primary cancer's location influences patients' survival rates, with left-sided colorectal cancer being associated with longer survival than right-sided colorectal cancer. This study aimed to explore the influence of the primary location of colorectal cancer on survival following brain metastasis.
    METHODS: To address this clinical question, we conducted a systematic review and meta-analysis. We included studies focused on patients diagnosed with brain metastasis from colorectal cancer. These studies reported survival outcomes based on different primary tumor sites (right versus left and colon versus rectum). The primary outcome was to aggregate the hazard ratio (HR) of left-sided colorectal cancer when metastasized to the brain compared with right-sided colorectal cancer. The secondary outcome was to aggregate the HR of rectal cancer when it metastasized to the brain compared with colon cancer.
    RESULTS: Ten studies with a total of 1792 patients were included in the meta-analysis, and combined HR was calculated. Left-sided colon cancer showed higher overall survival compared with right-sided colon cancer when metastasized to the brain (HR: 0.71, 95% CI: 0.54-0.94, I2 = 0%). Rectal cancer did not show a statistically significant difference in overall survival compared with colon cancer (HR: 0.75, 95% CI: 0.40-1.41, I2 = 81%).
    CONCLUSIONS: Concordant with lung and liver metastases, the primary location of colorectal cancer influenced overall survival when metastasized to the brain. Left-sided colon cancer demonstrated higher overall survival than right-sided colon cancer.
    Keywords:  Brain metastasis; Colorectal cancer; Left colon cancer; Rectal cancer; Right colon cancer
    DOI:  https://doi.org/10.1186/s40001-025-03614-z
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