bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2025–03–02
nine papers selected by
Maksym V. Kopanitsa, Charles River Laboratories



  1. Cancer Lett. 2025 Feb 21. pii: S0304-3835(25)00147-8. [Epub ahead of print] 217583
      Pancreatic cancer, characterized by its insidious onset, high invasiveness, resistance to chemotherapy, and a grim prognosis, with a five-year survival rate hovering below 10%. The identification of novel therapeutic targets addressing tumor progression is therefore critically important. While perineural invasion (PNI) is recognized as a pathological hallmark and key driver of pancreatic cancer progression, its role in metabolic reprogramming of malignant cells has not been fully elucidated. Using integrated metabolomics approaches, we found perineural invasion in pancreatic cancer significantly enhancing glycolytic flux of pancreatic cancer. Our data delineate a neuroendocrine-paracrine signaling axis in which neurturin secreted by neuronal cells binds to the GFRA2 receptor on pancreatic cancer cells, inducing RET kinase recruitment and subsequent heterodimer assembly. This receptor tyrosine kinase complex phosphorylates hexokinase 2 (HK2) at the evolutionarily conserved Ser122 residue, augmenting its hexokinase activity, ultimately driving aerobic glycolysis flux and fueling pancreatic cancer growth. In vivo experiments corroborate our findings, revealing that neurturin blockade effectively halts pancreatic cancer progression and synergizes with RET inhibitors. Our research underscores neurturin as a promising therapeutic target for the treatment of pancreatic cancer.
    Keywords:  Cancer neuroscience; Metabolism reprogram; Phosphorylation; Target therapy
    DOI:  https://doi.org/10.1016/j.canlet.2025.217583
  2. Cancer Lett. 2025 Feb 20. pii: S0304-3835(25)00127-2. [Epub ahead of print] 217563
      The peripheral nervous system significantly determines the fate of solid tumors and their microenvironment. In neurotropic malignancies such as pancreatic and prostate cancer, denervation in animal models demonstrate significantly delays in tumor initiation and progression, underscoring the critical neural dependency of these cancers. While tumor innervation establishes a structural basis for the neuromodulatory effects, the degree of innervation exhibits marked heterogeneity across tumor types, and its regulatory mechanisms remain poorly characterized. In this study, we screened genes associated with innervation status in pancreatic cancer and identified the splicing factor SRSF12 as a critical gene related to tumor innervation. In clinical samples, SRSF12 was expressed at low levels in pancreatic cancer tissues, and its downregulation was linked to poor prognosis in patients. Then we crossed Kras mutation and Srsf12 knockout mice (KrasG12DSrsf12fl/fl) together with Srsf12fl/flPdx1cre mice and found that depletion of Srsf12 accelerated Kras-driven pancreatic tumorigenesis and enhanced tumor innervation. Furthermore, we demonstrated that SRSF12 inhibits neurite outgrowth primarily by generating a LAMA3 splice isoform that lacks the fourth and fifth LG (G45) domains. Mechanistically, G45 promotes tumor innervation by activating ITGB1 and FAK in neurons. Together, our findings delineate SRSF12 as a novel suppressor of tumor innervation and pancreatic tumorigenesis, while also identifying a tumor-specific target for SRSF12-deficient pancreatic cancer.
    Keywords:  neural remodeling; pancreatic cancer; tumor innervation; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2025.217563
  3. Cancer Lett. 2025 Feb 25. pii: S0304-3835(25)00153-3. [Epub ahead of print] 217589
      The nervous system plays an important role in regulating physiological functions of the stomach, and its abnormal activity often impairs gastric homeostasis. In response to constant exposure to oncogenic stimuli that leads to gastric tumorigenesis, the neural system becomes an essential component of the tumor microenvironment via perineural infiltration, de novo neurogenesis, and axonogenesis, thereby driving cancer initiation and progression. In this review, we highlight emerging discoveries related to neural-cancer crosstalk and discuss how the nervous system is remodeled by tumor cells including neural components and modulators (including neurotransmitters and neuropeptides). Moreover, we provide a systematic analysis of neural control of the cellular hallmarks of cancer. Finally, we propose how the molecular circuits of neural-cancer crosstalk could be exploited as potential targets for novel anti-cancer treatment, providing new insights into a new modality of neural-based cancer therapeutic strategies.
    Keywords:  Axonogenesis; Neurogenesis; Neurotransmitter; Perineural infiltration; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2025.217589
  4. J Med Case Rep. 2025 Feb 27. 19(1): 78
       BACKGROUND: A hybrid nerve sheath tumor is a biphasic, benign neoplasm of peripheral nerve sheaths, consisting of combinations of neurofibroma, schwannoma, or perineurioma. These tumors were recognized only recently, in 2013; they commonly occur sporadically but rarely with syndromic associations, such as neurofibromatosis syndrome, Carney complex, and schwannomatosis. With an occurrence of 1 in every 33,000 individuals, neurofibromatosis type 2 is a rare autosomal dominant condition characterized by bilateral vestibular schwannomas. Herein we report a serendipitous occurrence of a hybrid nerve sheath tumor with neurofibromatosis type 2 syndrome, with an emphasis on its diagnostic mimics.
    CASE REPORT: A 35-year-old Indian male patient presented to the clinic with balance dysfunction, left-sided hearing loss, and spastic weakness in all four limbs during the past 6 months. Neurological examination revealed increased motor tone in all four limbs, bilateral 4/5 limb strength, a right grip strength of 80%, and a left grip strength of 90%. Romberg's sign, Babinski sign (extensor), and Hoffman's sign were positive. No cerebellar signs were elicited. A cranial nerve examination revealed bilateral hearing impairment, with hearing of the left being greater than that of the right. Magnetic resonance imaging revealed, an ependymoma at C1-2, a hyperintensive T2 lesion (likely a meningioma), a neurofibroma at C2, and bilateral vestibular schwannomas at the cerebellopontine angle. The patient underwent tumor excision surgery under somatosensory evoked potential/motor evoked potential monitoring. The tumor at the C2 level showed a nodular arrangement with typical schwannian nodules (SOX-10 strongly positive and epithelial membrane antigen negative); these nodules were encased by a hypocellular neurofibroma component (CD34+), forming a lattice around the former. No necrosis or increased proliferation index was noted.
    CONCLUSION: Neurofibromatosis type 2 syndrome is a rare condition, associated with mutations in both alleles of the NF2 (Merlin) gene, and is associated with meningiomas and ependymomas, as seen in this patient. Its occurrence alongside a spinal hybrid nerve sheath tumor is rare and can often lead to an erroneous diagnosis of other nerve sheath tumors or, rarely, a malignant nerve sheath tumor. This case highlights this rare confluence and its mimickers.
    Keywords:  HNST; Hybrid nerve sheath tumor; NF2; Neurofibromatosis; Spinal canal
    DOI:  https://doi.org/10.1186/s13256-025-05083-8
  5. Oncogene. 2025 Feb 27.
      Brain metastasis represents a significant challenge in oncology, driven by complex molecular and epigenetic mechanisms that distinguish it from primary tumors. While recent research has focused on identifying genomic mutation drivers with potential clinical utility, these strategies have not pinpointed specific genetic mutations responsible for site-specific metastasis to the brain. It is now clear that successful brain colonization by metastatic cancer cells requires intricate interactions with the brain tumor ecosystem and the acquisition of specialized molecular traits that facilitate their adaptation to this highly selective environment. This is best exemplified by widespread transcriptional adaptation during brain metastasis, resulting in aberrant gene programs that promote extravasation, seeding, and colonization of the brain. Increasing evidence suggests that epigenetic mechanisms play a significant role in shaping these pro-brain metastasis traits. This review explores dysregulated chromatin patterns driven by chromatin remodeling, histone modifications, DNA/RNA methylation, and other epigenetic regulators that underpin brain metastatic seeding, initiation, and outgrowth. We provide novel insights into how these epigenetic modifications arise within both the brain metastatic tumor and the surrounding brain metastatic tumor ecosystem. Finally, we discuss how the inherent plasticity and reversibility of the epigenomic landscape in brain metastases may offer new therapeutic opportunities.
    DOI:  https://doi.org/10.1038/s41388-025-03315-1
  6. Pharmaceuticals (Basel). 2025 Feb 16. pii: 262. [Epub ahead of print]18(2):
      Today, breast cancer (BC) is the most frequently diagnosed malignancy and a leading cause of cancer-related deaths among women worldwide. Brain metastases (BMs) are a common complication among individuals with advanced breast cancer, significantly impacting both survival rates and the overall condition of life of patients. This review systematically analyzes the innovative approaches to drug treatment for breast cancer brain metastases (BCBMs), with particular emphasis placed on treatments targeting molecular mechanisms and signaling pathways and drug delivery strategies targeting the blood brain barrier (BBB). The article discusses various drugs that have demonstrated effectiveness against BCBM, featuring a mix of monoclonal antibodies, nimble small-molecule tyrosine kinase inhibitors (TKIs), and innovative antibody-drug conjugates (ADCs). This study of various drugs and techniques designed to boost the permeability of the BBB sheds light on how these innovations can improve the treatment of brain metastases. This review highlights the need to develop new therapies for BCBM and to optimize existing treatment strategies. With a deeper comprehension of the intricate molecular mechanisms and advances in drug delivery technology, it is expected that more effective personalized treatment options will become available in the future for patients with BCBM.
    Keywords:  BBB; BCBM; CDK4/6inhibitors; Her2; LRP-1; NOTCH pathway; VEGF; WNT pathway; nanotechnology
    DOI:  https://doi.org/10.3390/ph18020262
  7. Nat Med. 2025 Feb 27.
      Brain metastases frequently develop in patients with non-small cell lung cancer (NSCLC) and are a common cause of cancer-related deaths, yet our understanding of the underlying human biology is limited. Here we performed multimodal single-nucleus RNA and T cell receptor, single-cell spatial and whole-genome sequencing of brain metastases and primary tumors of patients with treatment-naive NSCLC. Chromosomal instability (CIN) is a distinguishing genomic feature of brain metastases compared with primary tumors, which we validated through integrated analysis of molecular profiling and clinical data in 4,869 independent patients, and a new cohort of 12,275 patients with NSCLC. Unbiased analyses revealed transcriptional neural-like programs that strongly enriched in cancer cells from brain metastases, including a recurring, CINhigh cell subpopulation that preexists in primary tumors but strongly enriched in brain metastases, which was also recovered in matched single-cell spatial transcriptomics. Using multiplexed immunofluorescence in an independent cohort of treatment-naive pairs of primary tumors and brain metastases from the same patients with NSCLC, we validated genomic and tumor-microenvironmental findings and identified a cancer cell population characterized by neural features strongly enriched in brain metastases. This comprehensive analysis provides insights into human NSCLC brain metastasis biology and serves as an important resource for additional discovery.
    DOI:  https://doi.org/10.1038/s41591-025-03530-z
  8. Lung Cancer. 2025 Feb 19. pii: S0169-5002(25)00076-5. [Epub ahead of print]201 108455
       BACKGROUND: The combination of atezolizumab with etoposide and carboplatin (AECb) has become a new standard of care for extensive-stage small-cell lung cancer (ES-SCLC). This study evaluates its impact on central nervous system (CNS) progression, specifically brain metastases.
    METHOD: We analyzed the outcomes of 550 ES-SCLC patients who received first-line therapy between 2016 and 2022, focusing on time to intracranial progression (TTicP), progression-free survival (PFS), and overall survival (OS).
    RESULTS: Of the 550 patients, 247 (44.9 %) received AECb, while 303 (55.1 %) received conventional chemotherapy (CTx). Intracranial progression occurred in 179 patients (32.5 %), with the AECb group showing a significantly prolonged TTicP compared to the CTx group (median 24.4 vs. 14.3 months; p = 0.038). In patients without brain metastasis at diagnosis (n = 408), TTicP was also longer in the AECb group (27.2 vs. 15.3 months; p = 0.016). This benefit persisted even after excluding patients who underwent prophylactic cranial irradiation (PCI) (27.2 vs. 15.2 months; p = 0.02) (n = 394). These findings remained consistent after adjusting for age, initial metastatic site, and PCI. Additionally, the AECb group showed improved PFS (5.0 vs. 4.7 months; p = 0.004) and OS (11.1 vs. 9.8 months; p = 0.003).
    CONCLUSION: Our findings suggest that the AECb regimen is superior to conventional chemotherapy in delaying CNS progression and controlling systemic disease in ES-SCLC. These results support the AECb regimen as the new standard of care. Further research is needed to explore the mechanisms behind these improved CNS outcomes and to reassess the necessity of PCI in this treatment era.
    Keywords:  Atezolizumab; Brain metastasis; CNS outcomes; Extensive stage; Small cell lung cancer
    DOI:  https://doi.org/10.1016/j.lungcan.2025.108455
  9. Nat Med. 2025 Feb 27.
      Genomic profiling of central nervous system (CNS) metastases has the potential to guide treatments. In the present study, we included 584 patients with non-small-cell lung cancer and CNS metastases and performed a comprehensive analysis of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) with clinicopathological annotation. CSF ctDNA-positive detection was independently associated with shorter survival than negative detection (hazard ratio (HR) = 1.9, 95% confidence interval (CI) = 1.56-2.39; P < 0.0001). Matched tumor-CSF analysis characterized the CSF private molecular features causing poor survival (HR = 1.64, 95% CI = 1.15-2.32, P = 0.006). A multimetric CSF ctDNA prognostic model integrating CSF ctDNA features and clinical factors was developed for risk-stratifying CNS metastases and validated in an independent cohort. Among patients with treatment histories available, those positive for a driver alteration by CSF ctDNA showed a survival benefit from CSF-matched therapy (HR = 0.78, 95% CI = 0.65-0.92, P = 0.003). Longitudinal monitoring by CSF identified CNS-specific resistant mechanisms and a second matched targeted therapy indicating improved survival (HR = 0.56, 95% CI = 0.35-0.91, P = 0.018). These findings support the clinical value of CSF ctDNA for risk-stratifying CNS metastases and guiding therapy.
    DOI:  https://doi.org/10.1038/s41591-025-03538-5