bims-netuvo 2026-06-28 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2026–06–28
nine papers selected by
Maksym V. Kopanitsa, Charles River Laboratories

Varun Venkataramani: the rise of cancer neuroscience.
Pancreatic cancer fibrosis activates protumorigenic Schwann cells through a nuclear mechanosensing mechanism.
Neuron-Derived MIF Engages VCAM1 to Fuel a Self-Amplifying CXCL8 Loop That Drives Perineural Invasion and Metastasis in Gastric Cancer.
Nociceptor neurons suppress antitumor immunity in breast cancer.
Neuro-immune crosstalk in the tumor microenvironment: mechanisms and therapeutic implications for cancer immunotherapy.
Perineural invasion in intrahepatic cholangiocarcinoma: meta-analysis of prevalence, association with tumor features & impact on survival.
The Potential and Prospects of Marine Drugs in Intervening Nerve-Tumor Crosstalk.
Pan-Cancer Prognostic Analysis of NMDAR Genes Discovered Therapeutic Implications of Neuronal-Cancer Crosstalk Mediator GRIN2A for Small Cell Lung Cancer.
Genomic drivers of brain metastases in lung cancer.

Nat Rev Neurol. 2026 Jun 23.

Varun Venkataramani: the rise of cancer neuroscience.

Lisa Kiani, Varun Venkataramani.

DOI: https://doi.org/10.1038/s41582-026-01240-9
Gut. 2026 Jun 23. pii: gutjnl-2025-337316. [Epub ahead of print]

Pancreatic cancer fibrosis activates protumorigenic Schwann cells through a nuclear mechanosensing mechanism.

Pavel Stupakov, Golbahar Sadatrezaei, Ines Velazquez Quesada, Lillian A Boe, Chun-Hao Chen, Francesca Gaino, Efsevia Vakiani, Ihsan Ekin Demir, Boris Reva, Bojana Gligorijevic, Richard J Wong, Sylvie Deborde.

   BACKGROUND: Fibrosis and tumour innervation are two features of the tumour microenvironment (TME) that contribute directly to the lethality of pancreatic ductal adenocarcinoma (PDAC), but their potential interactions have not been explored. Moreover, although it is known that activated Schwann cells (SCs) stimulate cancer cell invasion, it remains unclear how SCs are activated.
OBJECTIVE: We determined how SCs are activated in the pancreatic fibrotic microenvironment.
DESIGN: The correlation between physical features of the microenvironment and SC activation was assessed in human patient samples and in mice by SC c-Jun phosphorylation monitoring, atomic force microscopy and multiphoton live imaging. Several in vitro models in which forces were applied to SCs expressing a reporter for c-Jun phosphorylation and RNA-Seq analysis were used to decipher the cellular and molecular mechanisms of SC activation.
RESULTS: Nerves surrounded by stiff stroma present higher SC activation. Intravital imaging shows a matrix-dependent SC activation. Mechanical forces on SCs induce c-Jun phosphorylation in SCs in a non-canonical manner that involves a nuclear sensing machinery with the pro-inflammatory enzyme phospholipase A2.
CONCLUSION: Fibrosis enhances the protumorigenic impact of innervation by activating SCs via a mechanism in which nuclear compression triggers non-canonical activation of the AP-1 transcription factor complex. Pancreatic fibrosis alone, without cancer cells, is sufficient to activate SCs, suggesting this mechanism may be common across non-malignant pancreatic diseases. Notably, SCs are more sensitive to mechanical activation than PDAC cells. These findings reveal TME interactions that may guide future microenvironment-targeted PDAC therapies.

Keywords:  FIBROSIS; NEUROBIOLOGY; PANCREATIC CANCER; PANCREATIC FIBROSIS; Schwann Cells

DOI:  https://doi.org/10.1136/gutjnl-2025-337316
Adv Sci (Weinh). 2026 Jun 22. e76195

Neuron-Derived MIF Engages VCAM1 to Fuel a Self-Amplifying CXCL8 Loop That Drives Perineural Invasion and Metastasis in Gastric Cancer.

Xunjun Li, Zhongya Zhai, Haiyi Yu, Renjie Qiu, Fengyu Li, Luxi Xiao, Boxi Huang, Huiying Liu, Jiayong He, Bowen Cai, Jiawen Chen, Jiang Yu, Guoxin Li, Tao Chen.

   BACKGROUND: Perineural invasion (PNI) is common in gastric cancer and predicts poor prognosis, but the molecular mechanisms underlying tumour-nerve crosstalk remain unclear.
METHODS: Transcriptomic data from TCGA and GEO were integrated to identify PNI regulators, with validation in surgical specimens. Mechanistic studies used tumor-neuron Transwell co-culture, siRNA/lentiviral perturbation, Western blot, immunofluorescence, ELISA, co-immunoprecipitation, and GST pull-down. Functional effects were assessed via CCK-8/Transwell assays, a sciatic nerve invasion xenograft model, and an orthotopic gastric cancer model with neuron-specific MIF conditional knockout mice.
RESULTS: High CXCL8/VCAM1 expression correlates with poor overall survival, distant metastasis, and is upregulated in PNI-positive tumours. Mechanistically, CXCL8 promotes neuronal MIF expression, while MIF directly binds VCAM1 and enhances tumour CXCL8 expression. VCAM1-mediated CXCL8 upregulation drives tumour proliferation and invasion. In vivo, blocking CXCL8/VCAM1 or neuron-specific MIF deletion reduces tumour growth and neural invasion.
CONCLUSIONS: A MIF-VCAM1-CXCL8 positive-feedback axis linking neural activity to gastric cancer progression and PNI is identified, providing prognostic biomarkers and actionable therapeutic targets.

Keywords:  gastric cancer; neural‐tumor interaction; perineural invasion; tumor proliferation and invasion

DOI:  https://doi.org/10.1002/advs.76195
Res Sq. 2026 Jun 09. pii: rs.3.rs-9927184. [Epub ahead of print]

Nociceptor neurons suppress antitumor immunity in breast cancer.

Sebastien Talbot, Yue Wu, Maryam Ahmadi, Ania Bogoslowski, Laura Brabenec, Jumana Abbadi, Beatriz Rocha, Amin Reza Nikpoor, Vera Thiel, Elisa Preto, Sheu Sulaiman, Migmar Tsamchoe, Alissa Dory, Lisa McIlvried, Tuany Eichwald, Tamara McErlain, Mohammad Balood, Christos Boutopoulos, Moutih Rafei, Paola Vermeer, Aeson Chang, Erica Sloan, Moran Amit, Josef Penninger, Uri Saragovi, Andreas Trumpp, Nicole Scheff, Karen Dixon, Maureen Cox, Alexander Birbrair, Jeremy C Borniger, Olga Bednova.

Peripheral nerves are emerging regulators of the tumor microenvironment, but how sensory innervation shapes breast cancer immunity remains poorly defined. Here we show that triple-negative breast cancers (TNBCs) co-opt nociceptor neurons to suppress antitumor immunity and promote disease progression. Across orthotopic TNBC models, we found that primary tumors and tumor-draining lymph nodes were densely innervated by CGRP⁺ sensory fibers. Tumor-derived cues directly activated dorsal root ganglion neurons, increased calcium responsiveness, induced Ngfr and Atf3, and triggered release of CGRP and substance P. Mechanistically, a tumor-derived proNGF-NGFR axis reprogrammed nociceptors and promoted neuropeptide secretion. Soluble mediators from activated nociceptors suppressed CD8⁺ T cell-mediated tumor-cell killing, whereas sensory-neuron silencing or ablation curtailed tumor growth and remodeled the immune microenvironment toward dendritic-cell activation, myeloid reprogramming, and enhanced CD8⁺ T cell and NK-cell effector states. Subset-specific analysis revealed nonredundant sensory control of immune states, with MrgD⁺ neurons selectively shaping macrophage-centered programs. Finally, blockade of CGRP signaling through RAMP1 reduced tumor growth and markedly enhanced PD-1 blockade, nearly eliminating primary tumor burden and lung metastasis in vivo. T cell-specific Ramp1 deletion similarly restrained tumor growth, and RAMP1⁺ CD8⁺ T cells in human TNBC displayed an exhaustion-associated phenotype. Together, these findings define a tumor-promoting proNGF-nociceptor-CGRP-RAMP1 axis and identify neuroimmune signaling as a therapeutically actionable vulnerability in TNBC.

DOI: https://doi.org/10.21203/rs.3.rs-9927184/v1
J Neuroinflammation. 2026 Jun 22.

Neuro-immune crosstalk in the tumor microenvironment: mechanisms and therapeutic implications for cancer immunotherapy.

Zezhi Fan, Na Wang, Bo Zhang, Kaiyuan Deng, Jiangjiang Fu, Li Ma, Junyi Li, Zhifang Xu, Yi Guo.

  The nervous system is a critical regulator of the tumor microenvironment (TME), extending beyond structural innervation to influence tumor initiation, progression, and therapeutic response. Neural regulation operates through synapse-like interactions and paracrine, neurotransmitter-mediated, and electrochemical signaling, thereby shaping both malignant and stromal compartments. These signals modulate immune-cell phenotypes, promote T-cell exhaustion, and expand immunosuppressive populations, thereby contributing to immune evasion and resistance to immunotherapy. Emerging evidence highlights bidirectional crosstalk, whereby neural activity supports tumor growth, metastasis, metabolic reprogramming, and immune suppression, while tumor-derived signals reciprocally remodel neural activity. This dynamic crosstalk defines a neuro-immune-tumor regulatory network that represents an important layer of tumor biology. Despite recent advances, how neural, immune, and metabolic pathways are integrated within the TME remains incompletely understood. Cancer neuroscience has therefore emerged as an interdisciplinary field for elucidating these mechanisms and identifying therapeutic vulnerabilities. Targeting the neuro-immune axis through neuromodulation, neuroactive agents, and combination immunotherapy may improve immunotherapy efficacy and advance precision oncology.

Keywords:  Cancer neuroscience; Immunotherapy; Neuro–immune crosstalk; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12974-026-03933-w
JHEP Rep. 2026 Jun 25. pii: S2589-5559(26)00210-7. [Epub ahead of print] 101939

Perineural invasion in intrahepatic cholangiocarcinoma: meta-analysis of prevalence, association with tumor features & impact on survival.

Johannes Kolck, Timo Alexander Auer, Camilla Winther Pedersen, Clarissa Hosse, Jana Ihlow, Felix Krenzien, Wenzel Schöning, Uli Fehrenbach, Dominik Geisel.

   BACKGROUND & AIMS: Perineural invasion (PNI) is a recognized marker of tumor aggressiveness in several malignancies, but its prevalence and prognostic significance in intrahepatic cholangiocarcinoma (ICC) remain uncertain. This systematic review and meta-analysis aimed to estimate the pooled prevalence of PNI and evaluate its association with overall survival (OS) in ICC.
METHODS: Following PRISMA guidelines, PubMed, Web of Science, and the Cochrane Library were searched through August 2025. PNI prevalence was pooled using a random-effects model. Where available, multivariable hazard ratios (HRs) for overall OS were pooled using a random-effects meta-analysis. Heterogeneity was assessed and potential moderators were explored using meta-regression. Pairwise ecological correlations between PNI and other tumor features were analyzed using Pearson's correlation coefficient.
RESULTS: Sixty-one studies including 15,502 patients were analyzed. The pooled prevalence of PNI was 36.0% (95% CI 31.0-41.0%), with substantial heterogeneity (I2 = 98.5%). Meta-regression identified publication year and study size as independent moderators, with more recent and larger studies reporting lower PNI prevalence. PNI was positively correlated with lymph node metastasis, lymphovascular invasion, and vascular invasion (all p < 0.001), and inversely correlated with the proportion of mass-forming ICC (p = 0.025). Of 44 studies assessing OS, 23 were included in meta-analysis, demonstrating that PNI was associated with worse survival (HR 1.79, 95% CI 1.38-2.19, p < 0.001).
CONCLUSIONS: PNI occurs in approximately one-third of patients with ICC, is associated with poorer outcomes, and clusters with LNM and VI, reflecting aggressive tumor biology. Despite the heterogeneity of the available data, its adverse prognostic impact is consistent.
IMPACT AND IMPLICATIONS: Perineural invasion (PNI) is a proposed marker of tumor aggressiveness in intrahepatic cholangiocarcinoma (ICC), yet its prevalence and prognostic significance have remained uncertain, warranting systematic evaluation. This study provides the most comprehensive synthesis to date of PNI in ICC demonstrating that PNI occurs in approximately one-third of ICC cases and clusters with adverse pathological features, although its independent impact on survival remains debatable. These findings are relevant for clinicians and researchers involved in ICC management, as they suggest that PNI may contribute to more refined risk stratification, particularly in early-stage disease. In practice, PNI assessment could support clinical decision-making and patient counseling, while future standardized and prospective studies are needed to clarify its prognostic value and potential role in guiding treatment strategies.

Keywords:  Biliary tract cancer; Biomarker; Curative resection; Hazard ratio; Hepatobiliary malignancy; Intraductal growth; Large-duct type; Liver malignancy; Mass-forming; Nerve sheath invasion; Node-negative disease; Outcome; PRISMA; Periductal-infiltrating; Prevalence; Prognosis; Small-duct type; Subtypes; Systematic review; Tumor biology

DOI:  https://doi.org/10.1016/j.jhepr.2026.101939
Mar Drugs. 2026 Jun 17. pii: 219. [Epub ahead of print]24(6):

The Potential and Prospects of Marine Drugs in Intervening Nerve-Tumor Crosstalk.

Dan Zhao, Ruiling Xu, Xinyan Xu, Jingxuan Tan, Zhili Zeng, Xirenayi Kanji, Xincan Li, Junchi Hu, Shuai Wang, Yongjun Dang.

  The bidirectional crosstalk between the nervous system and tumors has emerged as a transformative new frontier in both precision oncotherapy and mechanism-driven cancer pain management. Marine natural products with inherent neuroactive properties exhibit unparalleled intervention advantages for targeting this complex pathophysiological axis. Herein, we systematically and prospectively dissect the multi-layered bidirectional communication between the nervous system and malignancies, comprehensively summarize the pivotal contributions of marine-derived bioactive molecules to advances in neuroscience and antitumor therapeutics, and finally provide an outlook on and a call for integrated, interdisciplinary collaboration to enable transformative breakthroughs in the development of marine neuropharmacological agents targeting the nerve-tumor crosstalk axis.

Keywords:  cancer pain; marine drugs; nerve–tumor crosstalk; oncotherapy

DOI:  https://doi.org/10.3390/md24060219
Biomedicines. 2026 May 25. pii: 1196. [Epub ahead of print]14(6):

Pan-Cancer Prognostic Analysis of NMDAR Genes Discovered Therapeutic Implications of Neuronal-Cancer Crosstalk Mediator GRIN2A for Small Cell Lung Cancer.

Jiaxun Zhang, Akezhouli Shahatiaili, Yuhan Hou, Ning Zhou, Ke Huang, Xiaojun Wang, Dongmei Wang, Zhentao Yu, Xiaoli Feng, Yibo Gao.

  Background: As the most lethal neuroendocrine tumor, small cell lung cancer (SCLC) can drive its progression by hijacking neuronal mechanisms. At the core of this neural integration is the N-methyl-D-aspartate receptor (NMDAR) complex. However, its pan-cancer expression and clinical significance in SCLC remain poorly understood. Methods: We characterized NMDAR transcriptomic profiles across human cancers to develop the NMDAscore, and analyzed three independent European and Asian SCLC cohorts to identify prognostic biomarkers. Furthermore, we investigated the molecular mechanisms of GRIN2A and evaluated the efficacy of GluN2 inhibitors. Results: The developed NMDAscore exhibited significant prognostic correlations in ACC, COAD, KIRC, UVM, KIRP, OV, PCPG, UCS, THCA, THYM, HNSC, KICH, LGG, and PAAD. Focusing on the SCLC cohorts, we identified GRIN2A (encoding the GluN2A subunit) as a statistically relevant prognostic biomarker associated with poor survival. Mechanistically, GRIN2A upregulation correlates with the activation of neuro-synaptic signaling, metabolic reprogramming, genomic instability, and an immune-cold microenvironment characterized by CD8+ T cell exclusion. Pharmacological inhibition of GluN2 using dizocilpine and the FDA-approved antagonist memantine suppressed SCLC proliferation and tumorigenicity in vitro, in 3D tumor spheroids and in vivo xenograft models. Conclusions: Collectively, these findings establish GRIN2A as a prognostic biomarker, linking synaptic hijacking, metabolic plasticity, immune evasion, and drug resistance, and identify the therapeutic potentials of the GluN2 inhibitors dizocilpine and memantine for SCLC.

Keywords:  GRIN2A; NMDA receptor; cancer neuroscience; drug resistance; small cell lung cancer; tumor microenvironment

DOI:  https://doi.org/10.3390/biomedicines14061196
Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdag067

Genomic drivers of brain metastases in lung cancer.

Ting Wang, Hang Xing, Lei Huang, Hao Zhuang, Jianguo Zhang, Hong Ge, Bo Zhang, Yue Cao, Yining Zhai, Xiaoli Zheng, Shanshan Bu, Abbas E Abbas, Matthew Hadfield, Benedito A Carneiro, Liang Cheng, Yifei Liu.

Background: Brain metastases (BM) significantly affect both prognosis and quality of life in patients with metastatic non-small cell lung cancer (NSCLC), highlighting the need for innovative therapeutic strategies. In this systematic review, we evaluated the prevalence and clinical significance of key genomic alterations in BM from NSCLC.
Methods: Comprehensive searches of PubMed, Web of Science, Embase, and the Cochrane Library identified 19 studies encompassing 3028 patients, 930 of whom had BM.
Results: Among BM patients, 50% harbored TP53 mutations, while 49% exhibited PD-L1 overexpression, and 30% demonstrated a tumor mutational burden (TMB) ≥10 mut/Mb. These alterations were associated with tumor progression, immune evasion, and increased mutational load. Additional actionable biomarkers, though less frequent, included ERBB2, BRAF, and NTRK alterations. Importantly, our findings revealed substantial intertumor heterogeneity between primary tumors and BM, underscoring the need of site-specific genomic profiling to inform treatment decisions.
Conclusions: Overall, this study underscores the critical role of genomic profiling in advancing precision medicine approaches and supports the integration of novel targeted and immunotherapeutic strategies to improve outcomes in NSCLC patients with brain metastases. The dynamic evolution of biomarker expression during disease progression and tumor heterogeneity remains major challenges to the development of durable treatment strategies.

DOI: https://doi.org/10.1093/noajnl/vdag067