bims-netuvo 2026-07-05 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2026–07–05
eleven papers selected by
Maksym V. Kopanitsa, Charles River Laboratories

Molecular mechanisms and therapeutic targets in lung cancer-nerve crosstalk.
A dietary switch promotes sensory neuron-dependent cancer-associated cachexia.
Neural-tumor crosstalk in driving tumor metabolic reprogramming.
The tumor-nerve-immune electrical axis: A hypothesis-generating framework for electrochemical communication in cancer.
Stromal Regulation of Tumor Perineural Invasion: A Multicellular and Neuro-Ecological Perspective.
Neural regulation of cancer: from synaptic integration to neuro-immune regulation.
Preoperative prediction of lymphovascular and perineural invasion in locally advanced gastric cancer via CT habitat analysis and deep learning: A dual-center study.
What is the Relevance of Neuron-Tumor Interactions in Malignant CNS Tumors?
Macrophage-secreted brain-derived neurotrophic factor promotes tumor growth in triple-negative breast cancer by inducing axonogenesis.
Genomic Predictors of Perineural Invasion in Cutaneous Squamous Cell Carcinoma: Insights from an MD Anderson Cohort.
Electrophysiological markers of subclinical central nervous system involvement in patients with non-small-cell lung cancer without brain metastases.

Chin Med J Pulm Crit Care Med. 2026 Jun;4(2): 117-136

Molecular mechanisms and therapeutic targets in lung cancer-nerve crosstalk.

Ziyang Xu, Shanshan Huang, Qian Chu.

  Reciprocal crosstalk between the nervous system and malignancies is increasingly recognized as a key regulator of tumor progression across solid cancers. Neuronal activity and nerve infiltration can shape tumor growth, immune tone, and metastatic behavior through paracrine signaling and, in selected contexts, synapse-like interactions. However, how neural circuits regulate lung cancer progression remains insufficiently defined. β-adrenergic blockade has been reported to be associated with reduced lung tumor growth and metastatic potential in multiple settings, highlighting the clinical relevance of innervation. Here we synthesize emerging evidence on lung cancer-nerve crosstalk from the perspective of cancer neuroscience, focusing on neural remodeling in the tumor microenvironment, mechanisms underlying tumorigenesis and metastasis, the neuro-immune-tumor axis, and translational opportunities for neuro-modulatory interventions. This review provides an integrated framework to inform future mechanistic studies and the development of therapeutically actionable targets.

Keywords:  Cancer neuroscience; Lung cancer; Metastasis; Neuro–tumor crosstalk; β-adrenergic signaling

DOI:  https://doi.org/10.1016/j.pccm.2026.05.003
Science. 2026 Jul 02. 393(6806): 90-97

A dietary switch promotes sensory neuron-dependent cancer-associated cachexia.

Michael Cross, Stefan Kotschi, Warren Wu, Fedra Luciano-Mateo, Young-Yon Kwon, Ezequiel Dantas, Taha Niazi, Shijia Chen, Ali Rashidfarrokhi, Ray Pillai, Jack Sanford, Jeshua Kim, Juliya Hsiang, Begona Gamallo-Lana, Adam C Mar, Yuan Hao, Sahith Rajalingam, Annie Huang, Jackie Shan, Habon A Issa, Maria Gomez, Alice R Wang, Xiang Zhao, Tobias Janowitz, Eileen White, Yin Liu, Kwok-Kin Wong, Leopoldo N Segal, Sheng Hui, Marcus D Goncalves, Robert C Froemke, Thales Papagiannakopoulos.

Sickness behaviors are common in cancer-associated cachexia and affect up to half of lung cancer patients. We demonstrate that among the most common cancer mutations, loss of liver kinase B1 (Lkb1) promotes the development of cachexia in preclinical models of lung cancer. In an effort to improve caloric intake with an obesogenic high-fat diet, we paradoxically observed worsened cachexia-associated sickness. We found that local production of prostaglandin E2 (PGE2), rather than circulating factors, promotes sickness and that genetic, dietary, and pharmacological inhibition of tumor-derived PGE2 suppresses sickness and cachexia. Notably, we demonstrate that lung sensory neuron abrogation prevents PGE2-dependent cachexia. Our study establishes localized tumor-derived signals to sensory neurons, rather than circulating factors, as drivers of cachexia and highlights a previously unknown role of the peripheral nervous system in cancer cachexia.

DOI: https://doi.org/10.1126/science.adz4196
Biochim Biophys Acta Rev Cancer. 2026 Jun 28. pii: S0304-419X(26)00116-2. [Epub ahead of print]1881(4): 189644

Neural-tumor crosstalk in driving tumor metabolic reprogramming.

Xia Xiao, Congcong Zhang, Jiahao Chen, Jiayi Zhang, Hanyu Li, Weiming Yu, Xianlei Cai.

  Neural-tumor interactions have emerged as critical drivers of metabolic reprogramming in cancer. This review systematically examines how neural signaling reshapes tumor metabolism through a conceptual framework that classifies neural-tumor crosstalk into three principal modes: direct physical contacts, paracrine signaling, and indirect mediation via immune and glial cells. Key neurotransmitters (norepinephrine, acetylcholine, glutamate) and neurotrophic factors (NGF, BDNF) engage specific receptors on tumor cells, activating downstream signaling cascades that regulate glycolysis, lipid synthesis, and amino acid metabolism. Central to this axis is lactate, which not only fuels tumor growth but also drives histone lactylation, an epigenetic modification that links metabolic flux to sustained transcriptional reprogramming. Beyond the lactate-centered model, emerging mechanisms-including mitochondrial transfer via tunneling nanotubes, extracellular vesicle-mediated metabolic hijacking, and direct nutrient supply by neurons-reveal the remarkable diversity of neural-driven metabolic regulation. The neuro-immune-metabolic circuit adds another layer of complexity, whereby neural signals reprogram immune cell metabolism to create an immunosuppressive microenvironment. This review further evaluates therapeutic strategies targeting the neural-metabolic axis, from repurposed β-blockers to Trk inhibitors and metabolic interventions. By integrating these multifaceted interactions into a unified framework, we highlight future research directions and therapeutic opportunities that may yield novel treatments targeting the neural-metabolic interface in cancer.

Keywords:  Lactate; Metabolic reprogramming; Neural-tumor crosstalk; Neuro-immune-metabolic circuit; Tumor metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2026.189644
Biochim Biophys Acta Mol Basis Dis. 2026 Jun 27. pii: S0925-4439(26)00203-6. [Epub ahead of print]1872(7): 168340

The tumor-nerve-immune electrical axis: A hypothesis-generating framework for electrochemical communication in cancer.

Peng-Yu Zhao, Wei-Lin Jin.

  The tumor microenvironment (TME) is traditionally studied through biochemical, metabolic, and mechanical lenses. Increasing evidence, however, indicates that ion channels, membrane potential, and local ionic conditions also influence tumor and immune cell behavior, while cancer neuroscience has revealed that neural inputs can regulate tumor growth and plasticity. Despite these parallel advances, an integrated framework that explicitly links tumor bioelectricity, neural signaling, and immune electrochemical responsiveness is lacking. Here, we propose the tumor-nerve-immune electrical axis as a hypothesis-generating framework to organize these adjacent fields. We distinguish three levels of evidence: (i) compartment-specific mechanisms (tumor-cell bioelectricity, tumor-associated neural regulation, immune-cell electrophysiology), (ii) supported pairwise interactions (e.g., neuron-tumor coupling in selected cancers, extracellular K+-mediated T-cell suppression), and (iii) testable hypotheses that require direct experimental validation. The framework centers on three components, the electrical phenotype of cancer cells, activity-dependent signaling of tumor-associated nerves, and the capacity of immune cells to interpret ionic and membrane-state cues, and introduces the organizing concepts of neurogenic niche, electro-immunosuppression, and signal interception, all explicitly presented as testable heuristics rather than established universal mechanisms. Current evidence is strongest for individual components and selected pairwise interactions; direct demonstration of a broadly applicable tripartite electrical axis remains limited. We discuss experimentally testable predictions and therapeutic implications, including ion-channel-targeted pharmacology, physical field-based interventions, and emerging bioelectronic platforms. This framework is intended to guide mechanistic studies and evidence-based evaluation of when and how electrical communication contributes to cancer progression.

Keywords:  Bioelectricity; Bioelectronic medicine; Cancer neuroscience; Neuroimmunology; Tumor microenvironment; Tumor-nerve-immune electrical axis

DOI:  https://doi.org/10.1016/j.bbadis.2026.168340
Adv Sci (Weinh). 2026 Jun 28. e76248

Stromal Regulation of Tumor Perineural Invasion: A Multicellular and Neuro-Ecological Perspective.

Xiaoyang Lin, Yingqiao Liu, Haitao Lin, Kang Feng, Xiqiang Liu.

  Perineural invasion (PNI) is an aggressive driver of tumor progression, therapeutic resistance, and poor prognosis across diverse malignancies. Traditionally viewed as a tumor cell-autonomous process, PNI is increasingly recognized as a dynamic phenomenon shaped by the tumor-nerve-stromal ecosystem. This review synthesizes recent advances to reframe neural invasion as a coordinated, multicellular process governed by reciprocal interactions within this niche. We delineate how stromal and immune components, including cancer-associated fibroblasts, Schwann cells, immune cells, and the extracellular matrix, facilitate PNI through structural remodeling and biochemical signaling within the tumor-nerve interface. These coordinated interactions drive nerve reorganization and local immune reprogramming, collectively establishing a permissive niche that supports tumor spread along neural routes. By integrating these interconnected mechanisms into a neuro-ecological framework, we clarify how networked tumor-stromal-neural remodeling underlies neural dissemination. This perspective identifies therapeutic vulnerabilities within the neural microenvironment and suggests that disrupting bidirectional crosstalk between tumor cells and their stromal partners may offer strategies to limit neural spread and improve clinical outcomes.

Keywords:  cancer‐associated fibroblasts; perineural invasion; schwann cells; stromal regulation; tumor microenvironment

DOI:  https://doi.org/10.1002/advs.76248
Cell Oncol (Dordr). 2026 Jul 03.

Neural regulation of cancer: from synaptic integration to neuro-immune regulation.

Xiaomeng Li, Yuxin Li, Xiaoyan Shi, Yunyun Wang, Shaoping Ji.

  The emerging field of cancer neuroscience has reshaped our understanding of tumor biology, showing that the nervous system is an active participant in the tumor microenvironment. It modulates tumor progression through synaptic communication with cancer cells, paracrine signaling via neurotransmitters and neuropeptides, and indirect regulation of the tumor immune microenvironment. Recent discoveries have shown that neurons form synapses with brain tumors and peripheral cancers, driving tumor cell proliferation and invasion. Neurotransmitter and neuropeptide signaling activates pathways in cancer cells to promote malignancy. Furthermore, the nervous system shapes anti-tumor immunity by modulating T cells, natural killer cells, macrophages, and myeloid-derived suppressor cells, creating either an immunostimulatory or, more commonly, an immunosuppressive microenvironment that facilitates immune evasion and treatment resistance. The clinical significance of the neuro-immune-tumor axis is confirmed across multiple cancer types. Consequently, therapeutic strategies targeting neural regulation are emerging, including neurotransmitter receptor blockers, denervation techniques, neuromodulation devices, and approaches to remodel the immune landscape through neural signals. This review synthesizes how nerves regulate tumor progression via synaptic connections, neurotransmitter release, and immune modulation. We also summarize current and emerging therapeutic strategies aimed at disrupting or harnessing neuro-tumor communication. By integrating recent advances, this review aims to establish a framework for understanding neural regulation of cancer and to guide future research and clinical translation in this evolving field.

Keywords:  Cancer neuroscience; Neural regulation; Neuro-immune-tumor Axis; Synaptic connections; Tumor microenvironment

DOI:  https://doi.org/10.1007/s13402-026-01250-1
Eur J Radiol. 2026 Jun 24. pii: S0720-048X(26)00389-X. [Epub ahead of print]203 113041

Preoperative prediction of lymphovascular and perineural invasion in locally advanced gastric cancer via CT habitat analysis and deep learning: A dual-center study.

Lijia Bai, Yujie Bai, Yimin Guo, Miaoyan Zhu, Ming Wei, Hui Guo, Jianbo Gao, Ming Cheng.

   PURPOSE: To develop and validate a combined model integrating CT-based habitat analysis and deep learning (DL) features for the preoperative prediction of lymphovascular and perineural invasion (LVI/PNI) in locally advanced gastric cancer (LAGC).
METHODS: This dual-center, retrospective study included 611 LAGC patients divided into training (n = 374), internal validation (n = 161), and external validation (n = 76) cohorts. Radiomics and DL features were extracted from venous-phase CT images of the whole tumor to identify the optimal intratumoral signature. Additionally, K-means clustering was utilized to partition the tumors into distinct habitat subregions, from which DL features were extracted to select the optimal habitat signature. A combined model integrating the best intratumoral and habitat signatures with significant clinical factors was constructed via multivariate logistic regression and visualized as a nomogram. Performance was assessed using the area under the curve (AUC) and decision curve analysis (DCA).
RESULTS: The DL signature and the whole tumor (WT) habitat signature demonstrated superior discriminatory ability. Consequently, the combined model-integrating the DL signature, habitat WT signature, cT stage, and histological grade-achieved favorable predictive efficacy, yielding numerical improvements in AUC performance across all cohorts. AUC values were 0.891, 0.866, and 0.815 for the training, internal validation, and external validation cohorts, respectively. DCA confirmed that the model provided substantial net clinical benefit.
CONCLUSION: The proposed combined model provides a promising and clinically relevant tool for preoperative LVI/PNI risk assessment in LAGC, facilitating individualized treatment strategies.

Keywords:  Deep learning; Gastric cancer; Habitat analysis; Lymphovascular invasion; Perineural invasion

DOI:  https://doi.org/10.1016/j.ejrad.2026.113041
Neurology. 2026 Jul 28. 107(2): e218291

What is the Relevance of Neuron-Tumor Interactions in Malignant CNS Tumors?

Eduardo Benarroch.

Crosstalk between neurons and tumor cells strongly affects tumor growth, invasion, metastasis, and resistance to treatment. In the CNS, connections between neurons and malignant tumor cells promote cell proliferation. Glutamatergic or GABAergic neurons promote glioblastoma growth through neuron-to-glioma synapses and through activity-dependentparacrine signals. Glioblastoma cells form an interconnected network for signal propagation and synaptically integrate into neural circuits. Brain metastasis, for example, from breast cancer, acquire neuronal-like features within the neural microenvironment and also exploit neural circuitry by forming ''pseudotripartite synapses'' where cancer cells receive glutamatergic input facilitating their growth and colonization within the brain. These interactions between neurons and malignant cells in the CNS provide potential therapeutic targets.

DOI: https://doi.org/10.1212/WNL.0000000000218291
Cell Death Differ. 2026 Jul 02.

Macrophage-secreted brain-derived neurotrophic factor promotes tumor growth in triple-negative breast cancer by inducing axonogenesis.

Jumana Abbadi, Rameswari Velayutham, Anand C Annan, Amin Reza Nikpoor, Maryam Ahmadi, Beatriz G S Rocha, Jacob W Farriester, Jessica M Reel, Eric C Holland, Frank Szulzewsky, Alexander Birbrair, Kar-Ming Fung, Sebastien Talbot, Maureen A Cox.

Tumor-infiltrating nerves play critical roles in promoting tumor growth and progression; however, the mechanisms that drive tumor innervation remain unclear. Upon transformation, tumors recruit surrounding peripheral nerves into the tumor microenvironment (TME) to obtain their own innervation, a process called axonogenesis. While in vitro studies suggest tumor cell-derived neurotrophins, such as brain-derived neurotrophic factor (BDNF), drive axonogenesis, this has yet to be demonstrated in vivo. During wound healing, macrophages are the primary source of neurotrophins. Given the critical role of macrophages in breast cancer growth, we investigated whether these immune cells drive tumor axonogenesis in breast tumors in vivo. Syngeneic Py230 mouse triple-negative breast cancer (TNBC) cells were transplanted into intact mice and mice lacking immune-derived BDNF. Bone marrow-derived macrophages from either wild-type or immune-BDNF-deficient mice were transplanted into tumor-bearing recipients to determine if macrophage-derived BDNF was sufficient to restore tumor growth and innervation. We found that transplanted TNBC cannot grow in the absence of immune-derived BDNF, and that depletion of macrophages from the TME compromises tumor innervation. Remarkably, the introduction of wild-type macrophages restores tumor growth and innervation in mice lacking immune-derived BDNF, demonstrating that macrophages are both necessary and sufficient for tumor axonogenesis in vivo. In the absence of sensory tumor innervation, tumor growth was significantly reduced. Moreover, targeting BDNF signaling diminished TNBC growth and innervation. Our findings identify macrophages as the critical source of BDNF driving axonogenesis in breast cancer and suggest that selectively targeting BDNF signaling could provide a novel therapeutic strategy for treating TNBC through compromising tumor innervation.

DOI: https://doi.org/10.1038/s41418-026-01796-5
J Am Acad Dermatol. 2026 Jul 01. pii: S0190-9622(26)03025-2. [Epub ahead of print]

Genomic Predictors of Perineural Invasion in Cutaneous Squamous Cell Carcinoma: Insights from an MD Anderson Cohort.

Amber Loren O King, Victor Lee, Matthew J Davis, Matthew S Hayden, Jung Julie Kang, Christopher A Barker, Nancy Y Lee, Karen L Connolly, Matthew R LeBoeuf.



Keywords:  cBioPortal; clinicogenomic; cutaneous squamous cell carcinoma; genomic profiling; nodal metastasis; perineural invasion; recurrence; retrospective cohort study

DOI:  https://doi.org/10.1016/j.jaad.2026.06.128
Neurol Neurochir Pol. 2026 Jul 03.

Electrophysiological markers of subclinical central nervous system involvement in patients with non-small-cell lung cancer without brain metastases.

Karol Marschollek, Monika Kosacka, Maciej Majchrzak, Aneta Kowal, Sławomir Budrewicz, Anna Brzecka-Bonnaud, Anna Pokryszko-Dragan.

   AIM OF THE STUDY: To evaluate electrophysiological parameters of central nervous system (CNS) function in patients with non-small-cell lung cancer (NSCLC) without detectable CNS metastases.
CLINICAL RATIONALE FOR THE STUDY: Early recognition of nervous system involvement in lung cancer (LC) is important for the management of the disease. Evoked potentials are an objective and noninvasive method for assessing CNS bioelectrical activity, regarded as a useful tool in revealing subclinical CNS dysfunction in systemic diseases, including neoplasms.
MATERIAL AND METHODS: The study included 11 patients (mean age 67.3 years, 55% females), diagnosed with NSCLC, without CNS metastases, and a group of 24 healthy controls (HC) matched for age. All participants underwent brainstem auditory evoked potentials (BAEP), visual evoked potentials (VEP) and electroencephalography (EEG). Parameters of VEP and BAEP were compared between LC patients and HC. In the NSCLC group, they were also referred to the disease outcome evaluation after 12 months of follow-up.
RESULTS: In VEPs, patients with NSCLC had significantly longer median P100 and N145 latencies compared to the HC (112 vs. 104 ms, p < 0.001 and 158 vs. 145 ms, p = 0.002, respectively). In BAEPs, longer median latency of wave V and I-V interpeak latency were found in NSCLC patients (5.88 vs. 5.80 ms, p = 0.047 and 4.19 vs. 4.05 ms, p = 0.007, respectively); they also had significantly lower median amplitudes of I and V waves (0.13 vs. 0.25 μV, p < 0.001 and 0.29 vs. 0.39 μV, p = 0.001, respectively). In total, 10 out of 11 patients showed abnormalities in either VEP or BAEP: in 4 patients, delayed latencies or decreased amplitudes were detected for both modalities, in 4, only in BAEP and in 2, only in VEP. EEG abnormalities were detected in two patients in the NSCLC group. After 12 months of follow-up, in none of the patients brain metastases were revealed.
CONCLUSIONS AND CLINICAL IMPLICATIONS: This exploratory study demonstrated abnormalities of EP parameters in NSCLC patients, without otherwise detectable CNS involvement. These findings may suggest subclinical brain dysfunction in the course of NSCLC, although the underlying mechanism remains uncertain. The usefulness of electrophysiological methods in monitoring or predicting subtle neurological complications of NSCLC warrants further investigation.

Keywords:  brain metastases; brainstem auditory evoked potentials; electroencephalography; lung cancer; non–small cell lung cancer; visual evoked potentials

DOI:  https://doi.org/10.5603/pjnns.110593