bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2025–09–07
twelve papers selected by
Maksym V. Kopanitsa, Charles River Laboratories
  1. The Pdgfd-Pdgfrb axis orchestrates tumor-nerve crosstalk in pancreatic cancer.
  2. Cancer neuroscience of brain metastasis: When in Rome, do as the Romans do.
  3. Perineural invasion and the "cold" tumor microenvironment in pancreatic cancer: mechanisms of crosstalk and therapeutic opportunities.
  4. Novel approaches to clinical trial design in cancer neuroscience.
  5. Entangled cellular and molecular relationships at the sensory neuron-cancer interface.
  6. Next stop: Cancer neuroscience.
  7. Prognostic significance of perineural invasion and lymphovascular invasion following robot-assisted radical prostatectomy with negative surgical margins: a retrospective study from a high-volume center.
  8. Wired to spread: Neural regulation of metastasis.
  9. Cancer-related cognitive impairment: a review of National Institutes of Health‑Funded grants (2017-2024).
  10. EXPRESS: Exacerbation of paclitaxel-induced neuropathic pain behaviors in breast tumor-bearing mice.
  11. Exercise interventions in cancer-related cognitive impairment: an umbrella review.
  12. Mechanisms of cancer-induced neurophysiological dysfunction and therapeutic strategies.
  1. bioRxiv. 2025 Aug 31. pii: 2025.08.26.672505. [Epub ahead of print]
    The Pdgfd-Pdgfrb axis orchestrates tumor-nerve crosstalk in pancreatic cancer.
    Peter Wang, Nicole Lester, Ella Perrault, Jennifer Su, Dennis Gong, Carina Shiau, Jingyi Cao, Phuong Nguyen, Jung Woo Bae, Deniz Olgun, Hannah Hoffman, Ashley Lam, Jean Huang-Gao, Saifur Rahaman, Jimmy Guo, Jaimie Barth, Nicholas Caldwell, Prajan Divakar, Jason Reeves, Arya Bahrami, Shanshan He, Michael Patrick, Eric Miller, Maria Ganci, Grissel Cervantes-Jaramillo, Theodore Hong, Jennifer Wo, Hannah Roberts, Ralph Weissleder, Hongyoon Choi, Carlos Fernandez-Del-Castillo, Kathy Cormier, David T Ting, Tyler Jacks, Lei Zheng, Martin Hemberg, Mari Mino-Kenudson, William L Hwang.
      Nerves are an integral component of the tumor microenvironment, contributing to cancer progression, metastasis, morbidity, and mortality. In pancreatic ductal adenocarcinoma (PDAC), worse clinical outcomes are associated with perineural invasion (PNI), a process by which cancer cells surround and invade nerves. Here, we employed whole-transcriptome and single-cell spatial transcriptomics to identify candidate tumor-nerve interactions that promote PNI. We discovered that Pdgfd signaling promotes key features of nerve invasion. Mechanistically, Pdgfd stimulated cancer cell invasiveness, neurite outgrowth, and direct physical engagement with glia. Pharmacological blockade of this axis reduced each of these processes in vitro as well as PNI in vivo. Thus, Pdgfd-Pdgfrb signaling mediates PNI by coordinating multifaceted cancer-neuron-glia interactions and represents a promising therapeutic strategy aimed at disrupting harmful cancer-nerve crosstalk.
    DOI:  https://doi.org/10.1101/2025.08.26.672505
  2. Neuron. 2025 Sep 03. pii: S0896-6273(25)00588-4. [Epub ahead of print]113(17): 2740-2759
    Cancer neuroscience of brain metastasis: When in Rome, do as the Romans do.
    Matthia A Karreman, Frank Winkler.
      It is becoming increasingly clear that the nervous system and cancer execute an intimate crosstalk, influencing cancer initiation, growth, spread, and resistance mechanisms. Cancer, vice versa, can change the nervous system. These mostly harmful neuro-cancer interactions constitute the emerging field of "cancer neuroscience." Although this crosstalk is not limited to the central nervous system, the brain remains the site of particularly strong neural influences. In this review, we use the extensive knowledge of neuro-cancer interactions in primary brain tumors to highlight new discoveries about how neural influences govern metastatic tumor cells that originate from outside the brain and how, in turn, these cells can plastically modify the brain and its functions. Thus, we use brain metastasis, a particularly devastating complication of several common cancers, as a roadmap to conceptualize how far-reaching neuro-cancer interactions throughout the body can be and develop new ideas on how to use these insights for improved therapies.
    Keywords:  brain metastasis; brain tumor; cancer neuroscience; neurooncology
    DOI:  https://doi.org/10.1016/j.neuron.2025.08.003
  3. Front Immunol. 2025 ;16 1650117
    Perineural invasion and the "cold" tumor microenvironment in pancreatic cancer: mechanisms of crosstalk and therapeutic opportunities.
    Jianbiao Xu, Hong Yao, Junfeng Wang, Yun Jin, Wei Chang, Lanjiang Li, Lei Zou.
      Pancreatic ductal adenocarcinoma (PDAC) remains a devastating malignancy characterized by profound lethality, aggressive local invasion, dismal prognosis, and significant resistance to existing therapies. Two critical biological features underpin the challenges in treating PDAC: extensive perineural invasion (PNI), the process by which cancer cells infiltrate and migrate along nerves, and a profoundly immunosuppressive, or "cold," tumor microenvironment (TME). PNI is not only a primary route for local tumor dissemination and recurrence but also a major contributor to the severe pain often experienced by patients. Concurrently, the PDAC TME is typified by a dense desmoplastic stroma, hypoxia, and an abundance of immunosuppressive cells-including cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs)-while lacking sufficient infiltration of effector T cells, rendering it largely unresponsive to immunotherapies like checkpoint inhibitors. Although historically studied as separate entities, accumulating evidence reveals a deep-seated and complex bidirectional crosstalk between the neural components involved in PNI and the immune and stromal cells constituting the TME. Key cellular mediators, such as CAFs and TAMs, and shared signaling pathways, including the CXCL12/CXCR4 axis, TGF-β signaling, and neurotrophin pathways (e.g., NGF/TrkA), appear to act as critical nodes, coordinating the progression of PNI while simultaneously shaping and maintaining the immunosuppressive TME. This review synthesizes the current understanding of these intricate neuro-immune interactions in PDAC. We delineate the molecular and cellular mechanisms governing this crosstalk and explore how targeting these shared regulatory networks presents novel therapeutic opportunities, potentially disrupting PNI while concurrently "heating" the cold TME to overcome immunotherapy resistance. Elucidating this interplay is crucial not only for a deeper comprehension of PDAC's invasive and metastatic mechanisms but also for uncovering new therapeutic vulnerabilities to improve patient outcomes.
    Keywords:  CXCL12/CXCR4; cancer-associated fibroblasts; immunosuppression; neuro-immune crosstalk; pancreatic ductal adenocarcinoma; perineural invasion; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2025.1650117
  4. Neuron. 2025 Sep 03. pii: S0896-6273(25)00621-X. [Epub ahead of print]113(17): 2791-2813
    Novel approaches to clinical trial design in cancer neuroscience.
    Gregory Jones, Jennifer L Anderson, Phuong T T Nguyen, Frederico O Gleber-Netto, William L Hwang, Vinay K Puduvalli, Michelle Monje, Moran Amit.
      The emerging field of cancer neuroscience has revealed profound bidirectional interactions between the nervous system and cancer cells, identifying novel therapeutic vulnerabilities across diverse malignancies. This review examines the unique challenges and strategies for translating these insights into effective therapies. We propose innovative approaches to overcome these barriers through drug repurposing, enhanced biomarker development, and optimized trial designs. Repurposing neuroactive drugs with established safety profiles offers an accelerated path to clinical impact, particularly for targeting glutamatergic, adrenergic, and neurotrophic signaling pathways. Emphasizing mitigation of neurotoxicity and improved patient quality of life will be paramount moving forward. Repurposed agents that show preliminary potential for "dual use" (i.e., simultaneous toxicity mitigation and synergistic anti-tumor effects) are highlighted for special consideration. Master protocols and window-of-opportunity trials provide platforms to rapidly validate mechanisms while addressing patient-centered outcomes. By systematically addressing these foundational elements across disciplines, cancer neuroscience can translate its profound mechanistic insights into meaningful therapeutic advances for patients with treatment-resistant malignancies.
    DOI:  https://doi.org/10.1016/j.neuron.2025.08.015
  5. Neuron. 2025 Sep 03. pii: S0896-6273(25)00524-0. [Epub ahead of print]113(17): 2760-2790
    Entangled cellular and molecular relationships at the sensory neuron-cancer interface.
    Debpali Sur, Yi Zeng, Hiroki Kobayashi, Xiaofei Zhi, Mara R Goetz, Clara M Müller, Anastasia-Maria Zavitsanou, Caroline C Picoli, Andre A Martel Matos, Javier Pareja, Brajesh K Savita, Taeho Lee, Jair P Cunha-Junior, Jaime Henrique Amorim, Amin Reza Nikpoor, Alissa Dory, Ajitha Thanabalasuriar, Pedro A F Galante, Vincent T Ma, Aaron W James, Andrew J Shepherd, Madeleine J Oudin, Yuri L Bunimovich, Nicole N Scheff, Nisha J D'Silva, Karen O Dixon, Ishmail Abdus-Saboor, Timothy C Wang, Sebastien Talbot, Alexander Birbrair.
      Peripheral sensory neurons, once regarded merely as a passive route for nociceptive signals, are now acknowledged as active participants in solid tumor progression. This review explores how sensory neurons influence and are influenced by the tumor microenvironment (TME) through both chemical and electrical signaling, underscoring their pivotal role in the emerging field of cancer neuroscience. We summarize recent findings indicating that cancer-neuron interactions vary among different organs and experimental models, highlighting the ways in which various tumors recruit and reprogram sensory neurons to establish mutual communication loops that foster malignancy. Clinically, the degree of sensory innervation and the level of neuropeptide signaling show promise as diagnostic and prognostic biomarkers, while targeting these pathways may enhance the efficacy of standard cancer treatments. This review also highlights current knowledge gaps and proposes future research directions aimed at disrupting sensory neuron-tumor interactions, with the ultimate goal of improving clinical outcomes across multiple cancer types.
    Keywords:  cancer neuroscience; cancer progression; context-dependent roles; sensory neurons; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.neuron.2025.07.017
  6. Neuron. 2025 Sep 03. pii: S0896-6273(25)00596-3. [Epub ahead of print]113(17): 2725
    Next stop: Cancer neuroscience.
    Benedicte Babayan, Ted Dobie.
      
    DOI:  https://doi.org/10.1016/j.neuron.2025.08.011
  7. World J Urol. 2025 Sep 03. 43(1): 536
    Prognostic significance of perineural invasion and lymphovascular invasion following robot-assisted radical prostatectomy with negative surgical margins: a retrospective study from a high-volume center.
    Yu Ozawa, Rohan Sharma, Marcio Covas Moschovas, Shady Saikali, Ahmed Gamal, Marco Sandri, Travis Rogers, Vipul Patel.
       PURPOSE: Perineural invasion (PNI) and lymphovascular invasion (LVI) represent tumor escape mechanisms at radical prostatectomy (RP). We assessed their prognostic significance for biochemical recurrence (BCR) following complete resection.
    METHODS: We analyzed 10,471 men with negative surgical margins after RP, stratified into three groups based on pathological PNI and LVI status: Group 1 (PNI-/LVI-, n = 1,925), Group 2 (PNI+/LVI-, n = 7,849), and Group 3 (LVI+, n = 697; 14 with PNI-/LVI + and 683 with PNI+/LVI+). The cumulative probability of BCR (PSA > 0.2 ng/mL after initial undetectable level), cancer-specific mortality, and all-cause mortality were compared using Kaplan-Meier curves and log-rank tests. Multivariable Cox regression adjusted for age, race, comorbidity, PSA at biopsy, final grade group, pathological T and N stage, and tumor diameter.
    RESULTS: The median follow-up was 60 months (IQR: 18-108). Pathological N1 disease was more frequent in Group 3 (5.7%) than in Group 1 (0.1%) and Group 2 (0.3%). Compared with Group 1, the unadjusted hazard ratios (HRs) for BCR were 6.07 (95% CI: 4.30-8.56) in Group 2 and 23.4 (95% CI: 16.3-33.6) in Group 3; adjusted HRs were 2.51 (95% CI: 1.76-3.58) and 3.79 (95% CI: 2.55-5.53), respectively. Mortality outcomes were comparable across groups, both before and after the adjustment.
    CONCLUSION: Our study demonstrated that the combination of PNI and LVI independently predicted BCR following complete resection. Their integration into postoperative risk assessment may improve BCR prediction and guide individualized follow-up planning. Longer follow-up is required to draw definitive conclusions regarding their impact on mortality outcomes.
    Keywords:  Local; Margins of excision; Neoplasm recurrence; Neoplasm staging; Prostate-specific antigen; Prostatic neoplasms; Robotics
    DOI:  https://doi.org/10.1007/s00345-025-05749-4
  8. Neuron. 2025 Sep 03. pii: S0896-6273(25)00516-1. [Epub ahead of print]113(17): 2726-2728
    Wired to spread: Neural regulation of metastasis.
    Erica K Sloan, Aeson Chang.
      Neural signaling regulates multiple steps in the metastatic cascade. In this NeuroView, Sloan and Chang suggest that the neural landscape of metastatic microenvironments is highly dynamic and describe opportunities to target peripheral neuroplasticity for personalized anti-metastatic therapeutic interventions.
    DOI:  https://doi.org/10.1016/j.neuron.2025.07.009
  9. J Cancer Surviv. 2025 Sep 05.
    Cancer-related cognitive impairment: a review of National Institutes of Health‑Funded grants (2017-2024).
    Catherine A Schweppe, Rachel D Altshuler, Lori M Minasian, Nina S Kadan-Lottick.
       PURPOSE: Cancer-related cognitive impairment (CRCI) adversely affects cancer survivors' academic, occupational, and psychosocial functioning. Analyzing the National Institutes of Health (NIH) portfolio of funded research provides insight into current efforts, trends, and gaps in CRCI research.
    METHODS: We queried the internal NIH iSearch database to identify awards focused on CRCI. A total of 185 grants met inclusion criteria. Data were extracted from grant specific aims and methods. Awards were characterized by research stage (preclinical, clinical), cancer types, and treatments. Preclinical studies were coded for model type and cognitive assessments. Clinical studies were coded for trial design, inclusion criteria, cognitive outcomes, and biomarkers.
    RESULTS: Of 185 grants, 67% involved clinical, 30% preclinical, and 3% both human and animal studies. Commonly studied cancer types were breast (31%), central nervous system (25%), and hematological (22%). Chemotherapy (34%) and radiotherapy (23%) were the most examined therapies, while biologic (8%) and hormonal (6%) therapies were less frequently studied. Among 130 clinical studies, 64% had observational and 38% had interventional components. The 48 interventional studies focused on behavioral/complementary (73%), pharmacologic (25%), and/or device (10%) interventions. Most clinical studies assessed cognition with objective (88%) and patient-reported outcomes (76%) measures.
    CONCLUSION: Significant gaps persist in CRCI research related to high-incidence cancers such as prostate, lung, and colorectal, as well as in studies of emerging treatments like immunotherapy and hormonal therapy.
    IMPLICATIONS FOR CANCER SURVIVORS: Findings highlight unmet needs and opportunities to advance mechanistic and interventional research that supports cognitive health and quality of life for all cancer survivors.
    Keywords:  Cancer; Cancer-related cognitive impairment; Cognition; Funding
    DOI:  https://doi.org/10.1007/s11764-025-01890-6
  10. Mol Pain. 2025 Sep 05. 17448069251380034
    EXPRESS: Exacerbation of paclitaxel-induced neuropathic pain behaviors in breast tumor-bearing mice.
    Hee Kee Kim, Juping Xing, Youn-Sang Jung, Jae-Il Park, Hee Young Kim, Jimin Kim, Salahadin Abdi.
       BACKGROUND: Chronic pain and cancer interact bidirectionally, with pain enhancing sensory peptides and potentially promoting tumor growth. Despite this, most chemotherapy-induced neuropathic pain (CIPN) studies overlook the contribution of cancer itself to neuropathy, focusing instead on chemotherapy-induced mechanisms. Animal models of chemotherapy-induced neuropathic pain (CINP) have been developed by injecting chemotherapeutic drugs such as paclitaxel into normal animals without cancer. This study aimed to develop a new model in mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT) mice, a widely used breast cancer model with normal immune function.
    RESULTS: The percentage of positive response (PPR) of paclitaxel-injected MMTV-PyMT mice increased (about 20%; baseline, 10%) on day 4, reached the highest levels (50%-60%) on days 6-9, and then plateaued by day 29. In comparison, the PPR of paclitaxel-injected C57BL/6 was less than 10% on days 0-6, was about 40% on day 9, and then plateaued by day 29. Breast tumor-bearing mice exhibited an earlier onset and greater severity of paclitaxel-induced pain behaviors than tumor-free C57BL/6 mice. Systemic LGK-974 ameliorated paclitaxel-induced pain behaviors in MMTV-PyMT mice. Active β-catenin was detected in neurons and satellite cells of the dorsal root ganglia.
    CONCLUSIONS: Paclitaxel-induced neuropathic pain model in breast tumor-bearing female MMTV-PyMT mice may be a useful animal model for investigating the analgesic effects and underlying mechanisms for CINP in breast cancer patients as well as the interplay between CINP development and cancer progression.
    Keywords:  breast tumor; chemotherapy-induced neuropathic pain; neuropathic pain; paclitaxel
    DOI:  https://doi.org/10.1177/17448069251380034
  11. Am J Phys Med Rehabil. 2025 Aug 27.
    Exercise interventions in cancer-related cognitive impairment: an umbrella review.
    Chen Hu, Yanfang Zheng, Shuyan Xing, Xiangwen Han, Hao Gong, Jiyu Wang, Yang Yang, Huiyi Lv.
       PURPOSE: The aim of this umbrella review is to assess the effectiveness of exercise interventions in preventing and managing cancer-related cognitive impairment among cancer survivors, providing an evidence-based foundation for clinical practice.
    METHODS: The umbrella review was pre-registered on PROSPERO. It included systematic reviews that assessed any exercise interventions aimed at improving cognition in cancer patients. The overview adhered to gold-standard guidelines and recommendations. We utilized AMSTAR 2 to evaluate the quality of the literature and to synthesize the consistency of the evidence in order to formulate recommendations.
    RESULTS: Based on 28 systematic reviews, four subtypes of exercise interventions were identified. High-quality evidence consistently demonstrates that aerobic exercise significantly improves performance on specific neuropsychological tests. The Hopkins Verbal Learning Test (HVLT) shows a score improvement (SMD = 0.65, 95% CI: 0.42, 0.88); The Trail Making Test Part A (TMT-A) shows a reduction (SMD = -0.61, 95% CI: -0.92, -0.30). Mind-body exercises also have notable effects on alleviating subjective cognitive complaints, indicated by an improvement in the FACT-Cog score (SMD = 0.82, 95% CI: 0.49, 1.15). However, the evidence for objective cognitive improvement is limited and inconsistent. Combined training presents preliminary evidence of synergistic effects in enhancing global cognitive function, with an average effect across multiple cognitive domains (SMD = 0.45, 95% CI: 0.20, 0.70). Currently, resistance training lacks robust, high-quality evidence, and more studies are needed to determine its effects on specific objective cognitive domains.
    CONCLUSIONS: This review highlights exercise intervention as a key non-pharmacological approach for managing Cancer-Related Cognitive Impairment (CRCI). Urgent priorities for future research include: 1. Conducting high-quality randomized controlled trials (RCTs) to validate exercise tolerability in patients undergoing active treatment. 2. Developing multimodal assessment frameworks that integrate neuroimaging and blood-based biomarkers. 3. Establishing personalized exercise guidelines tailored to specific cancer types and treatment phases. Additionally, future studies should focus on clarifying the biological mechanisms that underpin the cognitive improvements associated with exercise. This will help create a stronger evidence base for precision exercise prescription.
    Keywords:  Cancer; Cancer-related cognitive impairment; Cognitive rehabilitation; Exercise Intervention; Umbrella review
    DOI:  https://doi.org/10.1097/PHM.0000000000002848
  12. Discov Oncol. 2025 Sep 03. 16(1): 1678
    Mechanisms of cancer-induced neurophysiological dysfunction and therapeutic strategies.
    Regan Mujinya, Elna Owembabazi, Ibe Michael Usman, Victor Bassey Archibong, Patrick Maduabuchi Aja, Daniel Chans Mwandah, Swase Dominic Terkimbi.
      Neurophysiological alterations represent a growing concern in oncology, affecting both the central and peripheral nervous systems through diverse mechanisms. These include direct tumor infiltration, paraneoplastic immune responses, systemic inflammation, metabolic dysregulation, and treatment-induced neurotoxicity. Neurological complications range from cognitive impairment and peripheral neuropathy to motor deficits and autonomic dysfunction. Paraneoplastic syndromes mediated by immune cross-reactivity and inflammatory cytokines such as IL-6 and TNF-α contribute to neural disruption. Cancer therapies, particularly chemotherapy, radiotherapy, and immunotherapy, increase these alterations, resulting in persistent or progressive neurological deficits. Diagnostic tools such as functional MRI, electroencephalography (EEG), cerebrospinal fluid biomarkers, and circulating tumor DNA (ctDNA) are used for earlier detection and reduced stratification risk. Management strategies incorporate neuroprotective agents (e.g., amifostine), cognitive rehabilitation, and non-invasive neuromodulation techniques. These techniques include transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). Personalized neuro-oncological care is guided by biomarker-driven profiling and digital health monitoring. Pediatric patients and long-term survivors require special attention due to vulnerability to neurodevelopmental disruption. A multidisciplinary and anticipatory approach is essential for preserving neurological function and enhancing quality of life across the cancer continuum. Advances in diagnostics and therapeutics are reshaping the integration of neurophysiology within comprehensive cancer care.
    Keywords:  Biomarkers; Cancer-related neurotoxicity; Cognitive dysfunction; Neuro-oncology; Neuroimaging; Paraneoplastic syndromes; Peripheral neuropathy; Rehabilitation
    DOI:  https://doi.org/10.1007/s12672-025-03520-0
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