bims-netuvo 2026-04-12 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2026–04–12
eleven papers selected by
Maksym V. Kopanitsa, Charles River Laboratories

Cancer Neuroscience: Innovative Conception and Emerging Strategy of Therapy.
Understanding nerve-tumor interactions: From basic biology to therapeutic innovation.
Sympathetic NPY signaling at the crossroads of neuro-tumoral metabolism.
Sex influences on tumor innervation.
Dual-layer spectral-detector CT-derived quantifications for preoperative identification of perineural invasion in gastric cancer.
Targeting ANXA1/TRKA axis enhances immunotherapy sensitivity in neural invasion-positive gastric cancer.
Prostaglandin E2-driven dedifferentiation of Schwann cells leads to perineural invasion in pancreatic ductal adenocarcinoma.
The Cell Surface Proteome of Malignant Peripheral Nerve Sheath Tumors Reveals Therapeutic Targets.
Malignant Peripheral Nerve Sheath Tumor of the Pancreas: A Case Report and Updated Review of Related Literature.
Brain Metabolic Activity Measured by [18F]FDG PET/CT Predicts Survival in Patients with Advanced Non-Small Cell Lung Cancer.
Emerging paradigms in the study of brain metastases.

MedComm (2020). 2026 Apr;7(4): e70708

Cancer Neuroscience: Innovative Conception and Emerging Strategy of Therapy.

Ting Wang, Zikai Dong, Yongfei Wang, Ziyi An, Siyuan Wang, Wei-Lin Jin.

  Cancer neuroscience has emerged as a paradigm-shifting discipline that reveals the active role of the nervous system in tumor development and progression. This review synthesizes current understanding of how bidirectional interactions between neurons and cancer cells influence tumorigenesis, metastasis, and therapy response. While earlier frameworks have established the fundamental mechanisms of nerve-tumor interactions, the present study proposes an expanded classification scheme that incorporates two additional mechanisms: perineural invasion as a unique metastatic pathway and neuro-microbic-oncology, which incorporates the gut-brain-immune axis into cancer biology. The remodeling of tumor microenvironment is structured around three principal mechanisms: electrochemical signaling, paracrine communication, and neuroimmune modulation. The contribution of these interactions to cancer-associated comorbidities, including pain, cachexia, and cognitive dysfunction, is highlighted, and their translational relevance is discussed in the context of emerging neurotherapeutic strategies. This review provides an integrated conceptual framework that connects neurobiology, oncology, and immunology, thereby informing the development of nerve-targeted therapeutic strategies with potential to improve clinical outcomes in cancer.

Keywords:  brain–body; comorbidity; drug repurposing; neuro‐microbic‐oncology; perineural invasion; tumor microenvironment

DOI:  https://doi.org/10.1002/mco2.70708
Genes Dis. 2026 Jul;13(4): 101955

Understanding nerve-tumor interactions: From basic biology to therapeutic innovation.

Liangzhan Sun, Xia Li, Yaxuan Wang, Jingxuan Wang, Renrui Xie, Ningyi Zhang, Zemin Zhang.

  The study of nerve-tumor interactions has emerged as a rapidly advancing and interdisciplinary field with profound implications for understanding cancer progression, prognosis, and therapeutic innovation. While this area holds significant promise for transformative discoveries, the mechanisms of nerve-tumor interactions and their translation into clinical applications remain at an early stage. This review focuses on the role of peripheral nerves in non-neurogenic solid tumors, discussing the prevalence and clinical impact of nerve-tumor interactions, their underlying forms and mechanisms, advancements in research technologies, therapeutic potential, and future challenges. By synthesizing current knowledge, integrating methodologies for studying nerve-tumor interactions, and identifying critical gaps, this work aims to provide a foundational resource to guide experimental design and stimulate interest in clinical trials targeting neural influences in cancer progression.

Keywords:  Cancer cell; Immune cell; Nerve; Tumor; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.gendis.2025.101955
Cell Metab. 2026 Apr 07. pii: S1550-4131(26)00098-7. [Epub ahead of print]38(4): 652-654

Sympathetic NPY signaling at the crossroads of neuro-tumoral metabolism.

Fernando Messore, Ana I Domingos.

Sympathetic neurons can co-release norepinephrine (NE) and neuropeptide Y (NPY). Contrary to its functions in the central nervous system, peripheral sympathetic NPY sustains energy expenditure and cellular proliferation. Here we discuss how tumors might co-opt this sympathetic influence to sustain their increased metabolism and proliferation.

DOI: https://doi.org/10.1016/j.cmet.2026.03.004
Biol Sex Differ. 2026 Apr 10.

Sex influences on tumor innervation.

Sarah M Barclay, Jeffrey Barr, Oduduabasi Isaiah, Mangalam Bajpai, Hailey Bullard, Ethan Neufeld, Craig C Welbon, Payal Ghosh, Destiny S Brockhaus, William C Spanos, Paola D Vermeer.

Peripheral solid malignancies are infiltrated by nerves. Using syngeneic cell lines, we set out to define whether sex influences tumor innervation in oral cancers and melanoma. Tumors grew significantly slower in females and were significantly more innervated than in males. In oral cancer, tumor-infiltrating nerves connect to a pre-existing neural circuit that enters the brain and impacts behavior. Thus, we evaluated the impact of sex on this circuit and assessed the behavioral consequences. We found no differences in the timing or extent of behavioral declines between oral tumor-bearing males and females. Moreover, in untreated mice, metastasis did not differ by sex. Treatment of oral tumors with cisplatin and radiation slowed tumor growth in male and female mice but significantly increased tumor innervation with females harboring the greatest innervation density. Treated females also harbored significantly increased metastases in their lungs compared to treated males. Treatment improved tumor-associated behavioral changes. While the tumor-brain circuit did not differ between males and females, the activation status of neurons and glia in projection areas significantly increased on the ipsilateral side. This heightened activation was attenuated following cisplatin/radiation treatment. These studies indicate that peripheral malignancies activate neurons and glia in central nervous system (CNS) projection areas, and that standard-of-care therapy attenuates this, which correlates with improved behavior. These findings emphasize that sex influences peripheral tumor-infiltrating nerves and brain function (via the tumor-brain circuit) and suggest that severing or silencing this circuit could improve patient outcomes.

DOI: https://doi.org/10.1186/s13293-026-00887-9
Eur J Radiol. 2026 Mar 30. pii: S0720-048X(26)00183-X. [Epub ahead of print]200 112835

Dual-layer spectral-detector CT-derived quantifications for preoperative identification of perineural invasion in gastric cancer.

Di-Xin Yao, Xiao-Xiao Lin, Xiao-Qiang Yao, Meng-Chen Yuan, Yi Wang, Jian-Bo Gao, Jing Li.

   OBJECTIVE: To investigate the utility of dual-layer spectral-detector CT (DLCT)-derived quantifications for preoperative identification of perineural invasion (PNI) in gastric cancer (GC).
METHODS: Between Feb 2023 and April 2024, 80 GC patients confirmed by surgical pathology who underwent preoperative multi-phase enhanced DLCT including arterial/venous/equilibrium phase (AP/VP/EP) were retrospectively included. Post-surgical pathology diagnosis of PNI was the reference standard, patients were divided into PNI-positive-or-negative accordingly. DLCT-based measurements, including iodine density (ID), normalized ID (nID), effective atomic number (Zeff), normalized Zeff (nZeff), arterial enhancement fraction (AEF1 based on AP/VP, AEF2 based on AP/EP), extracellular volume (ECV), were completed using two dimensional free-hand delineations at each phase and their differences were compared between different PNI groups. Independent predictors were screened and used to establish a combined parameter. Its performance was assessed using the receiver operating characteristic curve analysis and tested in an external dataset of 33 patients. Their associations with patient survival outcomes were explored by the Kaplan-Meier curve analysis in the primary dataset.
RESULTS: AEF1, nIDVP, and nZeffVP were independent predictors with similar AUCs of 0.666, 0.679, and 0.701, respectively. Their combination demonstrated superior performances with AUC achieving 0.865, 0.812, respectively for the primary and validation dataset. The risk-category defined by the combined parameter was associated with patient disease-free survival (χ2 = 5.012, p = 0.025) with hazard ratio being 3.462 (95% CI: 1.198-10.008) in the primary dataset.
CONCLUSION: DLCT-derived quantifications of AEF1, nIDVP, and nZeffVP are equally useful for identifying PNI in GC, their combination demonstrated incremental benefit and was associated with patient survival outcomes.

Keywords:  Perineural invasion; Stomach neoplasms; Tomography, X-ray Computed

DOI:  https://doi.org/10.1016/j.ejrad.2026.112835
Mol Biomed. 2026 Apr 09. pii: 48. [Epub ahead of print]7(1):

Targeting ANXA1/TRKA axis enhances immunotherapy sensitivity in neural invasion-positive gastric cancer.

Tianlu Jiang, Peng Zhou, Yikai Shen, Jie Lin, Ying Li, Xusheng Shen, Lang Fang, Penghui Xu, Zekuan Xu, Linjun Wang, Yiwen Xia.

  Gastric cancer (GC) remains a leading cause of cancer-related morbidity and mortality worldwide. Neural invasion (NI) is a common pathological behavior that worsens the prognosis in GC. However, the immune microenvironment of neural invasion-positive GC (NI+GC) and its potential therapeutic implications remain poorly defined. Here, we performed single-cell RNA sequencing (scRNA-seq) on tumor specimens from patients with NI+GC and neural invasion-negative GC (NI-GC) to comprehensively delineate the immune landscape. Our analysis revealed a significant enrichment of exhausted ANXA1+CD8+T cells within NI+GC tissues, which was validated by flow cytometry and multiplex immunohistochemistry assays. Clinically, patients with greater infiltration of ANXA1+CD8+ T cells had worse overall survival and disease progression. Mechanistically, ANXA1 bound to TRKA via N-terminal region, blocking NEDD4L-mediated ubiquitination and degradation of TRKA, thereby suppressing glycolytic metabolism and driving CD8⁺T cell exhaustion. Tumor-derived nerve growth factor (NGF) further amplified this exhaustion via TRKA engagement. Importantly, treatment with an ANXA1-derived peptide (A11) combined with TRKA inhibitors synergistically reversed T cell exhaustion and suppressed tumor growth in preclinical models. These findings unveil distinctive features of the immune microenvironment in NI+GC and elucidate the underlying molecular mechanisms of ANXA1/TRKA axis in facilitating immune evasion, which offer new insights for enhancing the sensitivity of immunotherapy to NI+GC patients.

Keywords:  ANXA1; Gastric cancer; Immune evasion; Neural invasion; T cell exhaustion; TRKA

DOI:  https://doi.org/10.1186/s43556-026-00444-1
Signal Transduct Target Ther. 2026 Apr 07. pii: 122. [Epub ahead of print]11(1):

Prostaglandin E2-driven dedifferentiation of Schwann cells leads to perineural invasion in pancreatic ductal adenocarcinoma.

Ling Wang, Qicai Liu, Zhibo Zhang, Shizhong Yang, Juan Tang, Guobin Pan, Yuqing Zheng, Yuting Zhuang, Qiming Wu, Shangeng Weng, Feng Gao, Jiahong Dong.

Perineural invasion (PNI), a prominent pathological feature of pancreatic ductal adenocarcinoma (PDAC), is closely associated with poor prognosis. Clarifying its mechanism is therefore critical for developing new therapies. Recent research has focused on the crosstalk between tumors and Schwann cells (SCs), particularly the role of SC dedifferentiation in facilitating PNI. In this study, by integrating RNA-seq, spatial transcriptomics, and single-cell analysis of clinical samples, we identified significant enrichment of dedifferentiated SCs and upregulation of key markers (p75NTR, SOX2, and c-Jun) in PNI regions. Moreover, PTGES was more highly expressed in the central region of the PNI than in the other regions of the PNI. Coculture experiments revealed that PANC-1 and BxPC-3 cells enhanced SC dedifferentiation, and this process facilitated pancreatic cancer cell malignancy. Furthermore, PTGES upregulation in the coculture system mediated prostaglandin E2 (PGE2) synthesis. Functional experiments revealed that PGE₂ drove morphological alterations in SCs-characterized by bipolar stretching-and elevated the expression of dedifferentiation markers, including p75NTR, c-Jun, SOX2, and GDNF. In the 3D coculture model, treatment with a PTGES inhibitor (CAY10526), siPTGES or PTGES-KO impaired the directional migration and neurite outgrowth of SCs toward PDAC cells. Mechanistically, PGE₂-stimulated SCs secrete elevated levels of LIF and ADAMTS-1, factors that promote extracellular matrix degradation and neural remodeling to facilitate tumor invasion. In summary, we delineate a novel paracrine axis in which PDAC-derived PGE₂ drives SC dedifferentiation and the production of proinvasive factors (LIF and ADAMTS-1), collectively establishing a microenvironment conducive to PNI. Our findings suggest that the PTGES-SC axis is a promising therapeutic target for inhibiting PNI in PDAC.

DOI: https://doi.org/10.1038/s41392-026-02648-x
bioRxiv. 2026 Mar 14. pii: 2026.03.11.711103. [Epub ahead of print]

The Cell Surface Proteome of Malignant Peripheral Nerve Sheath Tumors Reveals Therapeutic Targets.

Christopher M Stehn, Liangjun Wang, Zach Seeman, David A Largaespada.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas and the most common cause of disease-associated death for Neurofibromatosis Type 1 (NF1) patients. In the context of NF1, MPSNTs develop from benign premalignant precursors. The transition to malignancy is usually accompanied by loss of the polycomb repressive complex 2 (PRC2), leading to aberrant upregulation of many genes. The specific mechanisms disrupted by PRC2 loss remain incompletely understood. There is a significant gap in our knowledge of which cell-surface targets become derepressed and therapeutically actionable following PRC2 loss, contributing to the current lack of effective targeted therapies for MPNSTs. This study aims to address this gap by using cell-surface capture technology with mass spectrometry to profile MPNST models. In doing so, we define PRC2-dependent effects on the cell surface proteome, including specific biological pathways that are enhanced or suppressed at the cell surface protein level. We also create an MPNST cell-surface protein compendium comprised of proteins that are highly expressed across a variety of well-defined MPNST models. We prioritized proteins that are preferentially expressed in MPNST or other cancers and for which FDA-approved therapies already exist. Specific proteins from this compendium were molecularly targeted with antibody-drug conjugates in these models to surmise their therapeutic efficacy. Results reveal PTK7 as a novel and promising target for MPNST. In total, these efforts represent a step toward addressing the knowledge gap in MPNST genesis and identifying new therapeutic targets for further testing. Additionally, this data serves as a resource for other researchers wishing to characterize specific molecular targets.
KEY POINTS: PRC2 modulates key MPNST signaling pathways through the cell surface proteomeCell surface proteomics identifies a plethora of therapeutic targets for MPNST targeted therapyAntibody-drug conjugates targeting PTK7 show enhanced efficacy in reducing MPNST viability.
IMPORTANCE OF THE STUDY: This study utilizes advances in biochemistry to profile the surface proteome of malignant peripheral nerve sheath tumors. In doing so, it identifies many proteins whose presence is abundant on the cell surface of MPNST cells. Pre-clinical drug testing shows that use of antibody-drug conjugates may be effective in killing MPNST cells when targeted to epitopes identified in our MPNST cell surface proteome compendium. This study is a departure from more commonly used transcriptomic methods to identify cell surface proteins by using direct surface capture and mass spectrometry, providing a more direct measurement of cell surface protein abundance. Additionally, it identifies a handful of proteins which can be directly targeted pharmaceutically and one in particular, PTK7, whose targeting is highly effective in killing MPNST cells.

DOI: https://doi.org/10.64898/2026.03.11.711103
Acta Med Philipp. 2026 ;60(5): 135-143

Malignant Peripheral Nerve Sheath Tumor of the Pancreas: A Case Report and Updated Review of Related Literature.

Lea Roselle O De Castro, Vincent F Tatoy, Soriano I Capaya, Gracieux Y Fernando.

  Malignant peripheral nerve sheath tumors (MPNSTs) are rare soft tissue sarcomas with poor prognosis due to their high recurrence rates. The prevalence of MPNST in the general population is 0.001%, with tumors arising from the retroperitoneum accounting for only 1% of all MPNSTs. In this report, we present a case of a 59-year-old male with pancreatic MPNST. To the authors' knowledge, this is the first documented case of pancreatic MPNST in the Philippines. The patient initially presented with a 3-month history of abdominal pain, weight loss, and anorexia. On abdominal computed tomography (CT) scan, a large cystic mass involving the pancreatic head and body, with an enhancing peripheral solid component in the superior region was seen. The patient underwent distal pancreatectomy, en bloc splenectomy and excision of duodenal cyst. Post-operative histopathology and immunohistochemistry staining were consistent with pancreatic MPNST with tumor very near the margin of resection adjacent to the portal vein. Adjuvant systemic chemotherapy and radiotherapy were not performed due to lack of evidence of benefit over risk for this population. Disease recurrence (nodal-peritoneal metastases) was noted six months post-operatively and he was given palliative chemotherapy with single-agent doxorubicin. However, disease progression was noted after five cycles of chemotherapy. Second-line regimen was planned but the patient died of a pulmonary embolism prior to the initiation of chemotherapy. Due to the rarity and highly aggressive nature of MPNSTs, furthering knowledge on these tumors is important, particularly in their inclusion among the differential diagnoses for pancreatic tumors. Prompt diagnosis and histopathologic confirmation by a pathologist specializing in sarcomas are crucial in the treatment planning and prognostication of these tumors. Lastly, further studies are needed to establish more effective treatments in unresectable or metastatic disease.

Keywords:  malignant peripheral nerve sheath tumor; pancreas; sarcoma

DOI:  https://doi.org/10.47895/amp.vi0.13138
J Nucl Med. 2026 Apr 09. pii: jnumed.125.271400. [Epub ahead of print]

Brain Metabolic Activity Measured by [18F]FDG PET/CT Predicts Survival in Patients with Advanced Non-Small Cell Lung Cancer.

Julie Auriac, Ghada Lemoudda, Narinée Hovhannisyan-Baghdasarian, Manuel Pires, Lalith Kumar Shiyam Sundar, Paulette Salamoun-Feghali, Romain-David Seban, Nina Jehanno, Christophe Nioche, Marie Luporsi, Thomas Beyer, Alain Livartowski, Nicolas Girard, Irène Buvat, Fanny Orlhac.

  [18F]FDG PET/CT images play a key role in the management of patients with non-small cell lung cancer (NSCLC). In these scans, the focus is on detected tumors and their characteristics, neglecting information from other organs or tissues. We investigated whether the mean brain [18F]FDG uptake (brain SUVmean) is associated with overall survival (OS) in patients with advanced NSCLC. Methods: This retrospective study included patients with advanced NSCLC who underwent pretreatment [18F]FDG PET/CT scans between 2010 and 2023. Clinical and biologic data, tumor radiomic features, and brain SUVmean were collected. The ability of these features to predict OS was evaluated using univariable and multivariable Cox regression models. The correlation between brain SUVmean and clinical, imaging, and blood biomarkers was investigated using Spearman correlation coefficients. Results: Patients were chronologically divided into a discovery set (n = 234; mean age, 64 ± 11 y) and test set (n = 146; mean age, 66 ± 11 y). In the discovery set, univariable analysis showed that high brain SUVmean (greater than or equal to the median) was associated with longer OS (hazard ratio [HR], 0.83; 95% CI, 0.76-0.92; P < 0.001). Brain SUVmean was significantly lower in patients who died within 1 y compared with those who were still alive at the same time point (median brain SUVmean, 4.9 ± 1.4 vs. 5.7 ± 1.5, respectively; P < 0.001). Multivariable analysis revealed that brain SUVmean was an independent prognostic factor for OS (HR, 0.89; 95% CI, 0.80-0.98; P = 0.02), which was confirmed in the test set (P < 0.001). Brain SUVmean was independent of the radiomic features quantifying tumor involvement (r < 0.24, n = 380) and significantly correlated but complementary to several blood biomarkers including C-reactive protein (r = -0.37, n = 110 patients). The prognostic significance of brain SUVmean persisted in patients without brain metastases (P < 0.001). Conclusion: Low brain metabolic activity was associated with increased mortality in patients with advanced NSCLC. Brain SUVmean was an independent prognostic factor that may aid in patient stratification, although its interpretation requires further investigation.

Keywords:  18F-FDG PET/CT; non–small cell lung cancer; radiomics; survival

DOI:  https://doi.org/10.2967/jnumed.125.271400
Sci Signal. 2026 Apr 07. 19(932): eadj9726

Emerging paradigms in the study of brain metastases.

Shawn C Chafe, Daniel Mobilio, Kui Zhai, Agata M Kieliszek, Chitra Venugopal, Sheila K Singh.

Brain metastases arise from the spread of cancer cells from tumors residing outside the brain. Immunotherapy and molecularly targeted therapeutics have improved outcomes for some patients with brain metastases, but many patients are still faced with a dismal prognosis. The inability to effectively treat these tumors and improve patient survival highlights the dire need for improved therapeutic strategies that ultimately depend on developing a greater understanding of the molecular underpinnings and inner wiring of these tumors. In this Review, we discuss current and emerging insights into the genetics and cellular signaling pathways that contribute to the spread of tumors to the brain. We also discuss potential therapeutic targets in the metabolic vulnerabilities of cells that metastasize to the brain and in the interactions between metastases and the microenvironment.

DOI: https://doi.org/10.1126/scisignal.adj9726