bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2025–03–30
eleven papers selected by
Maksym V. Kopanitsa, Charles River Laboratories



  1. Mol Cell Biochem. 2025 Mar 27.
      The nervous system, which regulates organogenesis, homeostasis, and plasticity of the organism during human growth and development, integrates physiological functions of all organ systems, including the immune system. Its extensive network of branches throughout the body reaches the tumor microenvironment (TME), where it secretes neurotransmitters that directly regulate or influence immune cells. This, in turn, indirectly affects the occurrence, development, and metastasis of cancer. Conversely, cancer cells are now understood to secrete neurotrophic factors that remodel the nervous system. Targeting the cross-talk between the nervous system and cancer represents a promising strategy for cancer treatment, some aspects of which have been confirmed in clinical trials. This review addresses gaps in our understanding of the interaction between peripheral nerves and various human cancers. At the intersection of neuroscience and cancer biology, new targets for neuroscience-based cancer therapies are emerging, establishing a significant new pillar in cancer treatment.
    Keywords:  Cancer; Cancer treatment; Nervous system; Perineural invasion; Tumor neurobiology
    DOI:  https://doi.org/10.1007/s11010-025-05256-5
  2. Adv Sci (Weinh). 2025 Mar 27. e2501119
      Perineural invasion (PNI), characterized by tumor cells surrounding and invading nerves, is associated with poor prognosis in colorectal cancer (CRC). Understanding the mechanisms of PNI is crucial for developing targeted therapies to impede tumor progression. In this study, clinical information and transcriptome data are obtained from the TCGA database. Stable MAGEA6 knockdown CRC cell lines are established to investigate the impact of MAGEA6 on CRC malignancy. Immunohistochemical staining is used to assess the clinical significance of MAGEA6. Rectal orthotopic and sciatic nerve invasion models are employed to verify the role of MAGEA6 in PNI. Schwann cells (SCs) infiltration and recruitment by CRC cells are assessed using ssGSEA and co-culture experiments. The results reveal that MAGEA6 is a key regulator of PNI, with its expression correlating with poor prognosis. MAGEA6 knockdown reduces CRC cell migration, invasion, and PNI ability. Moreover, CRC cells recruit SCs, with CXCL1 promoting SCs migration. Mechanistically, MAGEA6 inhibits YY1 ubiquitination, stabilizing YY1 expression and enhancing SC recruitment via YY1-mediated CXCL1 transcription. These findings suggest that MAGEA6 enhances CRC invasiveness and PNI by stabilizing YY1, which upregulates CXCL1 secretion and promotes SC recruitment. This interaction underscores the critical role of MAGEA6 in PNI and highlights a potential therapeutic target in CRC.
    Keywords:  cancer neuroscience; melanoma‐associated antigen a6; perineural invasion; schwann cell; yin‐yang 1
    DOI:  https://doi.org/10.1002/advs.202501119
  3. Cancer Res. 2025 Mar 26.
      Perineural invasion (PNI) is a pivotal prognostic factor in pancreatic cancer associated with aggressive tumor behavior and adverse patient outcomes. The recognized clinical impact of PNI highlights the need to better understand the molecular mechanisms underlying PNI-induced phenotypes. In this study, we isolated PNI-associated cancer-associated fibroblasts (pCAFs), which demonstrated a markedly enhanced capacity to promote neural invasion in pancreatic cancer compared to non-perineural invasion-associated CAFs (npCAFs). Single-cell, high-throughput sequencing and metabolomics data showed a significant upregulation of glycolysis in pCAFs, fostering a high-lactate tumor microenvironment conducive to cancer progression. pCAF-derived lactate was absorbed by tumor cells, facilitating histone H3K18 lactylation. The lactate-induced epigenetic modification activated the transcription of neural invasion-associated genes, such as L1CAM and SLIT1, thereby driving PNI in pancreatic cancer. Further exploration of metabolic reprogramming in pCAFs revealed enhanced acetylation of the glycolytic enzyme GAPDH, which correlated with increased enzymatic activity and glycolytic flux. Targeting of GAPDH and lactylation modifications significantly inhibited neural invasion in a genetically engineered mouse model. Clinical data suggested that high levels of H3K18 lactylation correlate with severe PNI and poorer patient prognosis. Together, these findings provide critical insights into the role of CAFs in promoting PNI of pancreatic cancer, highlighting glycolytic reprogramming and lactate-driven histone modifications as potential therapeutic targets for PDAC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-3173
  4. J Exp Clin Cancer Res. 2025 Mar 22. 44(1): 103
       BACKGROUND: Perineural invasion (PNI) is a hallmark feature of pancreatic ductal adenocarcinoma (PDAC), which occurs at a high incidence and significantly contributes to PDAC lethality and poor survival. Despite its prevalence and association with poor prognosis, the molecular mechanisms underlying PNI in PDAC remain unclear.
    METHODS: We investigated clinical samples from two cohorts by UPLC/MS-MS to profiled significantly altered chemical RNA modifications in PDAC tissues with PNI lesions. Dorsal root ganglion coculture systems and sciatic nerve injection models validated PNI ability. We combined RNA-seq, acRIP-seq and ac4C-seq with CRISPR-based techniques to explore the regulatory mechanism of ac4C modification on the integrin beta 5 (ITGB5) transcript.
    RESULT: We reported that N4-acetylcytidine (ac4C) is a significantly altered chemical RNA modification in PDAC tissues with PNI lesions. In vitro and in vivo models demonstrated that tumor cells overexpression of N-acetyltransferase 10 (NAT10), the writer enzyme of mRNA ac4C modification, enhances PNI in PDAC. Further analysis revealed decreased ac4C levels on transcripts of the focal adhesion pathway, particular on ITGB5, in NAT10-knockdown PDAC cells. This ac4C modification in the CDS region of ITGB5 mRNA promotes its stability, subsequently activating the ITGB5-pFAK-pSrc pathway. CRISPR-based analysis further confirmed the crucial role of NAT10-mediated ac4C modification in regulating ITGB5 expression. Combining small-molecule inhibitors targeting NAT10 and focal adhesion kinase (FAK) significantly attenuated PNI in vivo.
    CONCLUSION: Our findings reveal a previously unrecognized ac4C-mediated epigenetic mechanism in PNI and propose a novel therapeutic strategy to improve survival in PDAC patients. NAT10 promotes PNI via ac4C modification in PDAC.
    Keywords:  Pancreatic ductal adenocarcinoma; Perineural invasion; RNA ac4C modification
    DOI:  https://doi.org/10.1186/s13046-025-03362-2
  5. Discov Oncol. 2025 Mar 26. 16(1): 396
      The nervous system plays a critical role in developmental biology and oncology, influencing processes from ontogeny to the complex dynamics of cancer progression. Interactions between the nervous system and cancer significantly affect oncogenesis, tumor growth, invasion, metastasis, treatment resistance, inflammation that promotes tumors, and the immune response. A comprehensive understanding of the signal transduction pathways involved in cancer biology is essential for devising effective anti-cancer strategies and overcoming resistance to existing therapies. Recent advances in cancer neuroscience promise to establish a new cornerstone of cancer therapy. Repurposing drugs originally developed for modulating nerve signal transduction represent a promising approach to target oncogenic signaling pathways in cancer treatment. This review endeavors to investigate the potential of repurposing neurological drugs, which target neurotransmitters and neural pathways, for oncological applications. In this context, it aims to bridge the interdisciplinary gap between neurology, psychiatry, internal medicine, and oncology. By leveraging already approved drugs, researchers can utilize existing extensive safety and efficacy data, thereby reducing both the time and financial resources necessary for the development of new cancer therapies. This strategy not only promises to enhance patient outcomes but also to expand the array of available treatments, thereby enriching the therapeutic landscape in oncology.
    Keywords:  Cancer treatment; Drug design; Drug repurposing; Nervous system
    DOI:  https://doi.org/10.1007/s12672-025-02067-4
  6. Cell Res. 2025 Mar 24.
      The emerging field of cancer neuroscience has demonstrated great progress in revealing the crucial role of the nervous system in cancer initiation and progression. Pancreatic ductal adenocarcinoma (PDAC) is characterized by perineural invasion and modulated by autonomic (sympathetic and parasympathetic) and sensory innervations. Here, we further demonstrated that within the tumor microenvironment of PDAC, nociceptor neurons interacted with cancer-associated fibroblasts (CAFs) through calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF). This interaction led to the inhibition of interleukin-15 expression in CAFs, suppressing the infiltration and cytotoxic function of natural killer (NK) cells and thereby promoting PDAC progression and cancer pain. In PDAC patients, nociceptive innervation of tumor tissue is negatively correlated with the infiltration of NK cells while positively correlated with pain intensity. This association serves as an independent prognostic factor for both overall survival and relapse-free survival for PDAC patients. Our findings highlight the crucial regulation of NK cells by nociceptor neurons through interaction with CAFs in the development of PDAC. We also propose that targeting nociceptor neurons or CGRP signaling may offer a promising therapy for PDAC and cancer pain.
    DOI:  https://doi.org/10.1038/s41422-025-01098-4
  7. Cell Death Dis. 2025 Mar 27. 16(1): 215
      Distal cholangiocarcinoma (dCCA) is a highly lethal malignancy that accounts for approximately 40% of patients with primary cholangiocarcinoma. Remarkable cellular heterogeneity and perineural invasion (PNI) are two typical features of dCCA. Deciphering the complex interplay between neoplastic and neural cells is crucial for understanding the mechanisms propelling PNI-positive dCCA progression. Herein, we conduct single-cell RNA sequencing on 24,715 cells from two pairs of PNI-positive dCCA tumors and adjacent tissues, identifying eight unique cell types. Malignant cells exhibit significant inter- and intra-tumor heterogeneity. We delineate the compositional and functional phenotypes of five Schwann cell (SC) subsets in PNI-positive dCCA. Moreover, our analyses reveal two potential cell subtypes critical to forming PNI: NEAT1+ malignant cells characterized by hypoxic propensity and GFAP+ dedifferentiated SCs featuring hypermetabolism. Further bioinformatics uncover extensive cellular interactions between these two subpopulations. Functional experiments confirm that lactate in the hypoxic tumor microenvironment can induce GFAP-dedifferentiation in SCs, which promotes cancer cell invasion and progression through upregulating HMGB1. Taken together, our findings offer a thorough characterization of the transcriptional profile in PNI-positive dCCA and unveil potential therapeutic targets for dCCA PNI.
    DOI:  https://doi.org/10.1038/s41419-025-07543-x
  8. Biomedicines. 2025 Mar 02. pii: 609. [Epub ahead of print]13(3):
      Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive primary malignancy, and recent technological advances in surgery have opened up more possibilities for surgical treatment. Emerging evidence highlights the critical roles of diverse immune and neural components in driving the aggressive behavior of PDAC. Recent studies have demonstrated that neural invasion, neural plasticity, and altered autonomic innervation contribute to pancreatic neuropathy in PDAC patients, while also elucidating the functional architecture of nerves innervating pancreatic draining lymph nodes. Research into the pathogenesis and therapeutic strategies for PDAC, particularly from the perspective of neuroimmune network interactions, represents a cutting-edge area of investigation. This review focuses on neuroimmune interactions, emphasizing the current understanding and future challenges in deciphering the reciprocal relationship between the nervous and immune systems in PDAC. Despite significant progress, key challenges remain, including the precise molecular mechanisms underlying neuroimmune crosstalk, the functional heterogeneity of neural and immune cell populations, and the development of targeted therapies that exploit these interactions. Understanding the molecular events governing pancreatic neuroimmune signaling axes will not only advance our knowledge of PDAC pathophysiology but also provide novel therapeutic targets. Translational efforts to bridge these findings into clinical applications, such as immunomodulatory therapies and neural-targeted interventions, hold promise for improving patient outcomes. This review underscores the need for further research to address unresolved questions and translate these insights into effective therapeutic strategies for PDAC.
    Keywords:  immune system; neuroimmune; neuroimmune interactions; pancreatic cancer; peripheral nervous system
    DOI:  https://doi.org/10.3390/biomedicines13030609
  9. Behav Brain Res. 2025 Mar 25. pii: S0166-4328(25)00142-1. [Epub ahead of print] 115556
       BACKGROUND: Peripheral tumors can alter the central nervous system activity leading to behavior alterations and cancer-related cognitive impairment (CRCI). Although commonly attributed to anti-cancer treatments, findings of CRCI in newly diagnosed cancer patients suggest that tumors alone may impair brain functions, including working memory and processing speed.
    METHODS: We assessed male and female mice behavior using a novel object recognition and a Y maze test along with the open field and burrowing tests. The tests were performed before and after tumor implantation (subcutaneous murine L5178Y-R lymphoma injection in the posterior hind limb), and through its progression to evaluate mobility, anxiety, motivation recognition, and spatial working memory.
    RESULTS: Male mice showed deficits in recognition memory, scoring a low novel object time exploration (42.26% in males [p = 0.02] and 50.15% [p = 0.53] in females). Spontaneous alternation was significantly impaired in both male (p = 0.01) and female (p = 0.03) mice. During tumor progression, only female mice showed decreased mobility in indicators such as average speed, mobility rate, and total distance in the open field test, as well as deficient burrowing activity, indicating a lack of motivation or sickness behavior. Our findings suggest that tumor burden is associated with behavioral alterations in a sex-dependent manner in a mouse model of lymphoma.
    Keywords:  CRCI; Cancer; behavior; cognitive impairment; lymphoma; sex differences
    DOI:  https://doi.org/10.1016/j.bbr.2025.115556
  10. World J Clin Cases. 2025 Mar 26. 13(9): 99421
       BACKGROUND: Small cell lung cancer (SCLC) is the most malignant type of lung cancer. Even in the latent period and early stage of the tumor, SCLC is prone to produce distant metastases with complex and diverse clinical manifestations. SCLC is most closely related to paraneoplastic syndrome, and some cases present as paraneoplastic peripheral neuropathy (PPN). PPN in SCLC appears early, lacks specificity, and often occurs before diagnosis of the primary tumor. It is easy to be misdiagnosed as a primary disease of the nervous system, leading to missed diagnosis and delayed diagnosis and treatment.
    CASE SUMMARY: This paper reports two cases of SCLC with limb weakness as the first symptom. The first symptoms of one patient were rash, limb weakness, and abnormal electromyography. The patient was repeatedly referred to the hospital for limb weakness and rash for > 1 year, during which time, treatment with hormones and immunosuppressants did not lead to significant improvement, and the condition gradually aggravated. The patient was later diagnosed with SCLC, and the dyskinesia did not worsen as the dermatomyositis improved after antineoplastic and hormone therapy. The second case presented with limb numbness and weakness as the first symptom, but the patient did not pay attention to it. Later, the patient was diagnosed with SCLC after facial edema caused by tumor thrombus invading the vein. However, he was diagnosed with extensive SCLC and died 1 year after diagnosis.
    CONCLUSION: The two cases had PPN and abnormal electromyography, highlighting its correlation with early clinical indicators of SCLC.
    Keywords:  Case report; Dermatomyositis; Electromyography; Paraneoplastic peripheral neuropathy; Peripheral neuropathy; Small cell lung cancer
    DOI:  https://doi.org/10.12998/wjcc.v13.i9.99421
  11. Cancer Lett. 2025 Mar 22. pii: S0304-3835(25)00233-2. [Epub ahead of print]619 217667
      Neurogenesis constitutes a pivotal facet of malignant tumors, wherein cancer and its therapeutic interventions possess the ability to reconfigure the nervous system, establishing a pathologic feedback loop that exacerbates tumor progression. Recent strides in high-resolution imaging, single-cell analysis, multi-omics technologies, and experimental models have opened unprecedented avenues in cancer neuroscience. This comprehensive review summarizes the latest advancements of these emerging technologies in elucidating the biological mechanisms underlying tumor initiation, invasion, metastasis, and the dynamic heterogeneity of the tumor microenvironment(TME), with a specific focus on neuron-glial-tumor interactions in glioblastoma(GBM) and other neurophilic cancers. Moreover, we innovatively propose target screening processes based on sequencing technologies and database frameworks. It rigorously evaluates ongoing clinical trial drugs and efficacy while spotlighting characteristic cells in the central and peripheral TME, consolidating cancer biomarkers pivotal for future targeted therapies and management strategies. By integrating these cutting-edge findings, this review aims to offer fresh insights into tumor-nervous system interactions, establishing a robust foundation for forthcoming clinical advancements.
    Keywords:  Cancer neuroscience; Cutting-edge technologies; Mechanisms; Nerve-tumor microenvironment; Strategies; Target screening
    DOI:  https://doi.org/10.1016/j.canlet.2025.217667