bims-netuvo 2025-08-10 papers

Cancer Cell. 2025 Aug 04. pii: S1535-6108(25)00325-3. [Epub ahead of print]

Rethinking relief: Targeting sensory neurons to combat cancer and pain.

Brian M Davis, Lisa A McIlvried, Jami L Saloman, Marci L Nilsen, Nicole N Scheff.

Cancer pain is a complex problem that, when left unaddressed, can impact overall survival and decrease patients' quality of life. Collaboration among medical oncologists, immunologists, and neurobiologists in the cancer neuroscience field has recently revealed a pivotal role for the sensory nervous system in cancer progression. We highlight recent scientific findings suggesting that selection of appropriate analgesics should consider not only their efficacy in reducing pain but also their potential to influence anti-tumor immunity and subsequent responses to immunotherapy.

DOI: https://doi.org/10.1016/j.ccell.2025.07.019

Trends Cancer. 2025 Aug 05. pii: S2405-8033(25)00173-6. [Epub ahead of print]

CGRP-mediated neural addiction in tumor dynamic remodeling.

Miaochun Xu, Yang Yu, Canhui Cao.

Neuro-tumor crosstalk is reshaping our understanding of cancer. Increasing data demonstrate that calcitonin gene-related peptide (CGRP) is a key neural driver of tumor growth, immune suppression, and cancer-associated symptoms, positioning CGRP-mediated neural addiction as a promising therapeutic target to disrupt tumor-nerve interactions and improve outcomes in patients with cancer.

Keywords: CGRP; cancer neuroscience; tumor microenvironment; tumor progression; tumorigenesis

DOI: https://doi.org/10.1016/j.trecan.2025.07.004

bioRxiv. 2025 Jul 26. pii: 2025.07.22.666151. [Epub ahead of print]

Triple-Negative Breast Cancer Cells Activate Sensory Neurons via TRPV1 to Drive Nerve Outgrowth and Tumor Progression.

Hanan Bloomer, Savannah R Parker, Audrey L Pierce, Wesley Clawson, Mallory M Caron, Thomas Gerton, Ankit Pandey, Thanh T Le, Tolulope Adewumi, Charlotte Kuperwasser, Michael Levin, Madeleine J Oudin.

The tumor microenvironment in triple-negative breast cancer (TNBC) is characterized by increased sensory nerve density, which contributes to cancer progression by promoting migration and metastasis. However, the origin of tumor-innervating nerves and the mechanisms driving sensory innervation into tumors remain poorly understood. Using in vivo retrograde labeling techniques, we show that mammary tumors are associated with an increase in nerves originating from the dorsal root ganglia. Additionally, we find that TNBC cells trigger stress and activation markers and induce neuronal firing in a transient receptor potential anilloid subtype 1 (TRPV1)-dependent manner. In both 2D and 3D cell culture models, TNBC cells promote outgrowth of sensory nerves that is abrogated with Trpv1 knockout. We identified c-Jun and IL-6 as an effector of neurite outgrowth that acts downstream of TRPV1 to promote outgrowth in vitro . Finally, in Trpv1 knockout mice, TNBC tumors exhibit delayed growth and reduced lung metastasis. These findings suggest that a critical role for TRPV1 in tumor-nerve crosstalk, offering a potential target to reduce metastatic disease.

DOI: https://doi.org/10.1101/2025.07.22.666151

bioRxiv. 2025 Jul 26. pii: 2025.07.22.666009. [Epub ahead of print]

Netrin-1 promotes pancreatic tumorigenesis and innervation through NEO1.

Nerves have been shown to regulate cancer progression. However, a clear demonstration of a role for axon guidance molecules in pancreatic tumorigenesis, innervation, and metastasis has been lacking. Using murine Kras G12D -mutant pancreatic organoids, we screened axon guidance molecules by qRT-PCR, identified Ntn1 upregulation, and then verified its in vivo upregulation during pancreatic tumorigenesis in humans and mice. NTN1 and its receptor NEO1 were upregulated in epithelial cells by the Kras mutation and β-adrenergic signaling, in part, through the MAPK pathway. Ex-vivo culture of celiac ganglia showed that NTN1 promoted the axonogenesis of sympathetic neurons through the nerve NEO1 receptor. In the Pdx1-Cre;LSL-Kras G12D/+ model, Ntn1 knockout decreased sympathetic innervation and the development of pancreatic intraepithelial neoplasia. Treatment of pancreatic tumor organoids with recombinant NTN1 enhanced cell growth, epithelial-mesenchymal transition (EMT), and cancer stemness with the upregulation of ZEB1 and SOX9 through NEO1-mediated activation of focal adhesion kinase (FAK). In Pdx1-Cre;LSL-Kras G12D/+ ;LSL-Trp53 R172H/+ mice, Ntn1 knockout reduced innervation, FAK phosphorylation, and the features of EMT and stemness to extend mouse survival. In a liver metastasis model of PDAC (pancreatic ductal adenocarcinoma), treatment with a NTN1-neutralizing antibody or tumoral knockdown of Neo1 reduced ZEB1 and SOX9 and decreased tumor progression. In contrast, Ntn1 overexpression promoted innervation and the progression of PDAC liver metastasis. These data suggest that the NTN1/NEO1 axis is a key regulator of PDAC progression, directly influencing cancer cell stemness and EMT, while indirectly promoting tumor growth through nerves. Inhibiting the NTN1/NEO1 axis could represent a potential therapeutic approach for PDAC.
Statement of Significance: NTN1 promotes pancreatic tumorigenesis and metastasis directly and indirectly through nerves, highlighting the importance of tumor cell-nerve crosstalk in cancer. NTN1 blockade could represent a promising strategy for treating PDAC liver metastasis.

DOI: https://doi.org/10.1101/2025.07.22.666009

Neuron. 2025 Jul 29. pii: S0896-6273(25)00509-4. [Epub ahead of print]

Social interaction in mice suppresses breast cancer progression via a corticoamygdala neural circuit.

Hui-Zhong Wen, Si-Yi Xiong, Yun-Xiao Lou, Si-Zhe Yang, Lin Sun, Yi-Lun Yi, Bo-Qin Tang, Qin Shu, Zhao-Qun Wang, Xiao-Jing Yan, Ya-Ran Wu, Peng-Hui Chen, Xiao-Wei Qi, Yi Zhang, Li-Meng Dai, Ying Xiong, Guang-Yan Wu.

Social behaviors are vital for all mammalian species. Clinical observations and epidemiological studies have demonstrated that social interaction (SI) may slow cancer progression and improve patient outcomes. However, the underlying neural mechanisms remain unknown. Here, we found that SI in mouse models suppresses tumor growth through activating glutamatergic inputs from the anterior cingulate cortex (ACCGlu) to the basolateral amygdala (BLA), inhibiting intratumoral sympathetic nerve activity. Chemogenetic inhibition of the SI-activated ACCGlu neurons and ACCGlu→BLAGlu circuits abolished anxiolytic and antitumor effects of SI. Artificial reactivation of these neurons and circuits could mimic the anxiolytic and antitumor effects of SI. Manipulating the ACCGlu→BLAGlu circuits to regulate intratumoral sympathetic activity and norepinephrine (NE) release affected tumor progression by modulating antitumor immunity. Collectively, our study shows that SI activates the corticoamygdala neural circuit, which suppresses cancer progression, offering potential insights into the clinical application of social support in cancer treatment.

Keywords: brain; breast cancer; cancer neuroscience; neural circuit; social interaction; tumor microenvironment

DOI: https://doi.org/10.1016/j.neuron.2025.07.002

Sci Signal. 2025 Aug 05. 18(898): eady6769

Tumor-derived small extracellular vesicles reprogram sensory nerves to drive immunosuppression in the tumor microenvironment.

Leah Boyd, Jeremy C Borniger.

Neuroimmune cross-talk is emerging as an important regulator of tumor growth and progression in cancers beyond the central nervous system. In this issue of Science Signaling, Restaino et al. demonstrate that tumor-derived small extracellular vesicles promote tumor growth by altering the secretory profile of infiltrating sensory neurons, generating a feed-forward loop that ultimately drives immunosuppression in the tumor microenvironment.

DOI: https://doi.org/10.1126/scisignal.ady6769

Adv Biol (Weinh). 2025 Aug 07. e00122

Intersection Between Local Anesthetics and Cancer Biology: What Now? Where Are We Going?

Eduardo Nunez-Rodriguez, Hao Zhang, Dhananjay Sah, Juan P Cata.

Local anesthetics (LAs), commonly used for regional and general anesthesia, have gained attention in recent years for their potential role during cancer curative surgery, as they may reduce cancer recurrence and progression. Studies in both laboratory and animal models have shown that LAs can inhibit tumor growth and cell proliferation, trigger apoptosis, and reduce metastasis by limiting cancer cell invasion and migration. In addition, LAs impact the tumor microenvironment by modulating inflammation, enhancing the immune response, blocking angiogenesis, and interfering with tumor innervation. The mechanisms behind these effects involve both voltage-gated sodium channel-dependent and independent pathways, such as AKT/mTOR, RAS/ERK, and SRC/STAT3, as well as regulating microRNAs, circular RNAs, and apoptosis-related proteins, among others. Furthermore, LAs may enhance the efficacy of chemotherapy and counteract chemoresistance. The aim of this review is to provide a comprehensive summary of the current literature on the various mechanisms through which LAs influence tumorigenesis, alter metastasis processes, modulate immune responses, and affect angiogenesis within the tumor microenvironment.

Keywords: cancer; local anesthetics; metastasis

DOI: https://doi.org/10.1002/adbi.202500122

Pain Physician. 2025 Jul;28(4): E403-E410

Comparison of Different Spinal Level Approaches in Splanchnic Sympathetic Neurolysis for Intractable Upper Abdominal Cancer Pain: A Retrospective Review.

Dhanalakshmi Koyyalagunta, Steven Mach, Matthew Chung.

BACKGROUND: Celiac plexus or splanchnic nerve neurolysis is a treatment modality commonly offered for cancer-related upper abdominal pain. The optimal spinal level for performing celiac/splanchnic sympathetic neurolysis remains unclear.
OBJECTIVE: We aimed to assess the outcome, effectiveness, and complications associated with undergoing splanchnic sympathetic neurolysis at various spinal levels for treating intractable upper abdominal cancer pain.
STUDY DESIGN: This is an analysis of a retrospective cohort.
SETTING: Pain management clinic at a large quaternary comprehensive cancer center.
METHODS: A retrospective chart review of patients with unremitting cancer-related upper abdominal pain refractory to medical management was performed. Data were collected on pertinent demographic, clinical characteristics, cancer diagnosis and staging, location of abdominal pain, pain Numeric Rating Scale (NRS-11) scores, prior cancer treatments, level/laterality of splanchnic neurolysis, agents and volumes used for neurolysis, adverse events, pre- and postprocedure daily morphine milligram equivalents (MME), and symptom burden/quality-of-life outcomes.
RESULTS: A total of 254 patients treated with splanchnic sympathetic neurolysis for intractable upper abdominal cancer pain from July 2014 through June 2017 were included. Of the splanchnic sympathetic neurolysis procedures performed, most were done at T12 (44%) and L1 (54%)., The vast majority were bilateral (96%) using absolute alcohol (98%). There was no significant difference in MME requirements at postprocedure 6-months. Additionally, while NRS-11 scores improved at postprocedure one month and 6 months compared to baseline, there was no significant difference in NRS-11 scores based on the level at which the procedure was performed. A subgroup analysis of patients (n = 201 observations) with cancer pain related to intraabdominal viscera innervated by the splanchnic nerves (i.e., pancreatic, hepatobiliary, renal/adrenal, and gastrointestinal tract) also revealed that block level was not significantly associated with pain score. Time was a significant factor associated with NRS-11 score; patients had a significantly decreased pain score at postprocedure one month and 6 months. For patients with abdominal cancers of predominately splanchnic innervation, splanchnic sympathetic neurolysis also improved quality of life measures such as nausea, feeling of wellbeing, and mental clarity.
LIMITATIONS: One-third of the patients in our study were lost to follow-up at 3 months, likely due to the patient population with end-stage cancer, the natural history of cancer disease progression, or death.
CONCLUSION: The majority of splanchnic sympathetic neurolysis were performed at L1 and T12. Improved pain scores were comparable between block levels and provided sustained pain relief for at least 6 months. Significant changes in daily MMEs were demonstrated with neurolysis in association with the one month follow-up. While we found that splanchnic sympathetic neurolysis was effective in reducing opioid requirements, larger randomized studies are needed to look for any meaningful difference in long-term efficacy for pain control and side effects for splanchnic nerve sympathetic neurolysis.

Keywords: abdominal pain; cancer pain; celiac plexus; neurolysis; spinal level ; Splanchnic