Pub Date : 2025-09-02DOI: 10.1126/scisignal.adu8839
Daozhong Jin, Hong Chen, Meng-Hua Zhou, Yuying Huang, Shao-Rui Chen, Hui-Lin Pan
Opioids relieve pain by activating μ-opioid receptors (MORs), which inhibit communication between pain-sensing neurons (nociceptors) and the spinal cord. However, prolonged opioid use can paradoxically lead to increased pain sensitivity (hyperalgesia) and reduced analgesic efficacy (tolerance), partly because of the activation of NMDA-type glutamate receptors (NMDARs) at the central terminals of primary sensory neurons in the spinal cord. Here, we identified a critical role for the G protein Gαq in this paradox. Pharmacological inhibition of Gαq in rats reversed morphine-induced increases in NMDAR phosphorylation, synaptic trafficking, and activity at sensory neuron terminals and reduced morphine-induced excitatory nociceptive input to spinal dorsal horn neurons. Morphine enhanced Gαq coupling specifically to metabotropic glutamate receptor 5 (mGluR5) dimers in the spinal cord. Furthermore, targeted knockdown of Gαq in dorsal root ganglion neurons in mice normalized NMDAR-related changes and prevented NMDAR-mediated synaptic potentiation triggered by MOR activation. In addition, either pharmacological or genetic disruption of Gαq signaling enhanced morphine’s analgesic effects while reducing hyperalgesia and tolerance. These findings reveal that Gαq signaling contributes to opioid-induced NMDAR hyperactivity at nociceptor central terminals by promoting MOR-mGluR5 cross-talk. Targeting this pathway may improve the safety and efficacy of opioid-based pain management.
{"title":"Gαq signaling in primary sensory neurons shifts opioid analgesia to NMDA receptor–driven tolerance and hyperalgesia","authors":"Daozhong Jin, Hong Chen, Meng-Hua Zhou, Yuying Huang, Shao-Rui Chen, Hui-Lin Pan","doi":"10.1126/scisignal.adu8839","DOIUrl":"10.1126/scisignal.adu8839","url":null,"abstract":"<div >Opioids relieve pain by activating μ-opioid receptors (MORs), which inhibit communication between pain-sensing neurons (nociceptors) and the spinal cord. However, prolonged opioid use can paradoxically lead to increased pain sensitivity (hyperalgesia) and reduced analgesic efficacy (tolerance), partly because of the activation of NMDA-type glutamate receptors (NMDARs) at the central terminals of primary sensory neurons in the spinal cord. Here, we identified a critical role for the G protein Gα<sub>q</sub> in this paradox. Pharmacological inhibition of Gα<sub>q</sub> in rats reversed morphine-induced increases in NMDAR phosphorylation, synaptic trafficking, and activity at sensory neuron terminals and reduced morphine-induced excitatory nociceptive input to spinal dorsal horn neurons. Morphine enhanced Gα<sub>q</sub> coupling specifically to metabotropic glutamate receptor 5 (mGluR5) dimers in the spinal cord. Furthermore, targeted knockdown of Gα<sub>q</sub> in dorsal root ganglion neurons in mice normalized NMDAR-related changes and prevented NMDAR-mediated synaptic potentiation triggered by MOR activation. In addition, either pharmacological or genetic disruption of Gα<sub>q</sub> signaling enhanced morphine’s analgesic effects while reducing hyperalgesia and tolerance. These findings reveal that Gα<sub>q</sub> signaling contributes to opioid-induced NMDAR hyperactivity at nociceptor central terminals by promoting MOR-mGluR5 cross-talk. Targeting this pathway may improve the safety and efficacy of opioid-based pain management.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 902","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adu8839","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-26DOI: 10.1126/scisignal.aeb6175
Annalisa M. VanHook
Estrogen protects against kidney injury through both genomic and nongenomic mechanisms.
雌激素通过基因组和非基因组机制保护肾脏免受损伤。
{"title":"Estrogen-powered kidney protection","authors":"Annalisa M. VanHook","doi":"10.1126/scisignal.aeb6175","DOIUrl":"10.1126/scisignal.aeb6175","url":null,"abstract":"<div >Estrogen protects against kidney injury through both genomic and nongenomic mechanisms.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 901","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144905652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-26DOI: 10.1126/scisignal.adu7253
Sangeevan Vellappan, Junhong Sun, John Favate, Pranavi Jagadeesan, Debbie Cerda, Premal Shah, Srujana S. Yadavalli
Bacterial small proteins (≤50 amino acids) are an emerging class of regulators that modulate the activity of signaling networks that enable bacterial adaptation to stress. The Escherichia coli genome encodes at least 150 small proteins, most of which are functionally uncharacterized. We identified and characterized 17 small proteins induced in E. coli during magnesium (Mg2+) starvation using ribosome profiling, RNA sequencing, and transcriptional reporter assays. Several of these were transcriptionally activated by the PhoQ-PhoP two-component signaling system, which is crucial for Mg2+ homeostasis. Deletion or overexpression of some of these small proteins led to growth defects and changes in cell size under low-Mg2+ conditions, indicating physiological roles in stress adaptation. The small transmembrane protein YoaI, which was transcriptionally induced by the phosphate-responsive PhoR-PhoB signaling pathway, increased in abundance under Mg2+ limitation independently of yoaI transcription or PhoQ-PhoP signaling. YoaI activated a third signaling system, EnvZ-OmpR, which mediates responses to osmotic stress. Overall, this study establishes an initial framework for understanding how small proteins contribute to bacterial stress adaptation by facilitating cross-talk between different signaling systems. Our results suggest that these proteins play broader roles in coordinating stress responses, reflecting the interconnected nature of cellular stress networks rather than strictly compartmentalized pathways responding to specific stressors.
{"title":"Analysis of stress-induced small proteins in Escherichia coli reveals that YoaI mediates cross-talk between distinct signaling systems","authors":"Sangeevan Vellappan, Junhong Sun, John Favate, Pranavi Jagadeesan, Debbie Cerda, Premal Shah, Srujana S. Yadavalli","doi":"10.1126/scisignal.adu7253","DOIUrl":"10.1126/scisignal.adu7253","url":null,"abstract":"<div >Bacterial small proteins (≤50 amino acids) are an emerging class of regulators that modulate the activity of signaling networks that enable bacterial adaptation to stress. The <i>Escherichia coli</i> genome encodes at least 150 small proteins, most of which are functionally uncharacterized. We identified and characterized 17 small proteins induced in <i>E</i>. <i>coli</i> during magnesium (Mg<sup>2+</sup>) starvation using ribosome profiling, RNA sequencing, and transcriptional reporter assays. Several of these were transcriptionally activated by the PhoQ-PhoP two-component signaling system, which is crucial for Mg<sup>2+</sup> homeostasis. Deletion or overexpression of some of these small proteins led to growth defects and changes in cell size under low-Mg<sup>2+</sup> conditions, indicating physiological roles in stress adaptation. The small transmembrane protein YoaI, which was transcriptionally induced by the phosphate-responsive PhoR-PhoB signaling pathway, increased in abundance under Mg<sup>2+</sup> limitation independently of <i>yoaI</i> transcription or PhoQ-PhoP signaling. YoaI activated a third signaling system, EnvZ-OmpR, which mediates responses to osmotic stress. Overall, this study establishes an initial framework for understanding how small proteins contribute to bacterial stress adaptation by facilitating cross-talk between different signaling systems. Our results suggest that these proteins play broader roles in coordinating stress responses, reflecting the interconnected nature of cellular stress networks rather than strictly compartmentalized pathways responding to specific stressors.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 901","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144905651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-19DOI: 10.1126/scisignal.adt8127
Sandra E. Gostynska, Jordan A. Karim, Bailee E. Ford, Peyton H. Gordon, Katie M. Babin, Asuka Inoue, Nevin A. Lambert, Augen A. Pioszak
Three amylin receptors (AMYRs) mediate the metabolic actions of the peptide hormone amylin and are drug targets for diabetes and obesity. AMY1R, AMY2R, and AMY3R are heterodimers consisting of the calcitonin receptor (CTR), a G protein–coupled receptor, paired with a RAMP1, RAMP2, or RAMP3 accessory subunit, respectively, which increases amylin potency. Here, we found that the AMYRs had distinct basal subunit equilibria that were modulated by peptide agonists and determined the extent of cAMP signaling downstream of receptor activation. By developing a biochemical assay that resolves the AMYR heterodimers and free subunits, we found that the AMY1R and AMY2R subunit distributions favored free CTR and RAMPs and that rat amylin promoted association of the constituent subunits of AMY1R and AMY2R. The agonist αCGRP also induced AMY1R subunit association. A stronger interaction between the CTR and the RAMP3 transmembrane domains yielded a more stable AMY3R, and human and salmon calcitonin agonists promoted AMY3R dissociation. Similar changes in subunit association and dissociation were observed in live-cell membranes, and G protein coupling and cAMP signaling assays showed how these changes altered signaling. Our findings have implications for AMYR biology and drug development and reveal regulation of heteromeric GPCR signaling through subunit interaction dynamics.
{"title":"Amylin receptor subunit interactions are modulated by agonists and determine signaling","authors":"Sandra E. Gostynska, Jordan A. Karim, Bailee E. Ford, Peyton H. Gordon, Katie M. Babin, Asuka Inoue, Nevin A. Lambert, Augen A. Pioszak","doi":"10.1126/scisignal.adt8127","DOIUrl":"10.1126/scisignal.adt8127","url":null,"abstract":"<div >Three amylin receptors (AMYRs) mediate the metabolic actions of the peptide hormone amylin and are drug targets for diabetes and obesity. AMY<sub>1</sub>R, AMY<sub>2</sub>R, and AMY<sub>3</sub>R are heterodimers consisting of the calcitonin receptor (CTR), a G protein–coupled receptor, paired with a RAMP1, RAMP2, or RAMP3 accessory subunit, respectively, which increases amylin potency. Here, we found that the AMYRs had distinct basal subunit equilibria that were modulated by peptide agonists and determined the extent of cAMP signaling downstream of receptor activation. By developing a biochemical assay that resolves the AMYR heterodimers and free subunits, we found that the AMY<sub>1</sub>R and AMY<sub>2</sub>R subunit distributions favored free CTR and RAMPs and that rat amylin promoted association of the constituent subunits of AMY<sub>1</sub>R and AMY<sub>2</sub>R. The agonist αCGRP also induced AMY<sub>1</sub>R subunit association. A stronger interaction between the CTR and the RAMP3 transmembrane domains yielded a more stable AMY<sub>3</sub>R, and human and salmon calcitonin agonists promoted AMY<sub>3</sub>R dissociation. Similar changes in subunit association and dissociation were observed in live-cell membranes, and G protein coupling and cAMP signaling assays showed how these changes altered signaling. Our findings have implications for AMYR biology and drug development and reveal regulation of heteromeric GPCR signaling through subunit interaction dynamics.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 900","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144870112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-19DOI: 10.1126/scisignal.adq8279
Terrance Lam, Bailey Cardwell, Bonan Liu, Cheng Peng, Mia Spark, Sandra Sursock, Cameron J. Nowell, Andrew M. Ellisdon, Aeson Chang, Alastair C. Keen, Erica K. Sloan, Michelle L. Halls
Noradrenaline released from sympathetic neurons accelerates cancer metastasis by activating β2-adrenergic receptors (β2-adrenoceptors) on tumor cells to promote invasion. We previously showed that the β2-adrenoceptor promotes invasive behavior in a metastatic triple-negative breast cancer (TNBC) cell line by activating a cAMP- and calcium-mediated feedforward loop. Here, we found this mechanism in most TNBC lines that have an active β2-adrenoceptor. Integrated analysis of transcriptomic datasets revealed HOXC12, which encodes a developmental homeobox transcription factor, as the most discriminating gene separating cell lines with the feedforward loop and those without it. The high expression of HOXC12 did not correlate with transcriptional changes in integral proteins associated with cAMP or calcium signaling, and immunostaining showed cytosolic localization of Hox-C12, suggesting that it played a nontranscriptional role. Knocking out HOXC12 prevented β2-adrenoceptor–mediated calcium signaling and invasion in cultured TNBC cells. In basal breast cancers, HOXC12 expression in tumors negatively correlated with overall and disease-free survival in patients. These findings identify a key mediator, Hox-C12, in the coordination of invasion driven by cAMP and calcium signaling in β2-adrenoceptor–responsive TNBC cells.
{"title":"Hox-C12 coordinates β2-adrenoceptor coupling to a cAMP/calcium feedforward loop to drive invasion in triple-negative breast cancer","authors":"Terrance Lam, Bailey Cardwell, Bonan Liu, Cheng Peng, Mia Spark, Sandra Sursock, Cameron J. Nowell, Andrew M. Ellisdon, Aeson Chang, Alastair C. Keen, Erica K. Sloan, Michelle L. Halls","doi":"10.1126/scisignal.adq8279","DOIUrl":"10.1126/scisignal.adq8279","url":null,"abstract":"<div >Noradrenaline released from sympathetic neurons accelerates cancer metastasis by activating β<sub>2</sub>-adrenergic receptors (β<sub>2</sub>-adrenoceptors) on tumor cells to promote invasion. We previously showed that the β<sub>2</sub>-adrenoceptor promotes invasive behavior in a metastatic triple-negative breast cancer (TNBC) cell line by activating a cAMP- and calcium-mediated feedforward loop. Here, we found this mechanism in most TNBC lines that have an active β<sub>2</sub>-adrenoceptor. Integrated analysis of transcriptomic datasets revealed <i>HOXC12</i>, which encodes a developmental homeobox transcription factor, as the most discriminating gene separating cell lines with the feedforward loop and those without it. The high expression of <i>HOXC12</i> did not correlate with transcriptional changes in integral proteins associated with cAMP or calcium signaling, and immunostaining showed cytosolic localization of Hox-C12, suggesting that it played a nontranscriptional role. Knocking out <i>HOXC12</i> prevented β<sub>2</sub>-adrenoceptor–mediated calcium signaling and invasion in cultured TNBC cells. In basal breast cancers, <i>HOXC12</i> expression in tumors negatively correlated with overall and disease-free survival in patients. These findings identify a key mediator, Hox-C12, in the coordination of invasion driven by cAMP and calcium signaling in β<sub>2</sub>-adrenoceptor–responsive TNBC cells.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 900","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adq8279","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144870111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-12DOI: 10.1126/scisignal.aeb2685
John F. Foley
Positive allosteric modulators of free fatty acid receptor 2 induce distinct conformations to bias G protein signaling.
游离脂肪酸受体2的正变构调节剂诱导不同构象偏向G蛋白信号。
{"title":"Tailored receptor modulators","authors":"John F. Foley","doi":"10.1126/scisignal.aeb2685","DOIUrl":"10.1126/scisignal.aeb2685","url":null,"abstract":"<div >Positive allosteric modulators of free fatty acid receptor 2 induce distinct conformations to bias G protein signaling.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 899","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-12DOI: 10.1126/scisignal.ads7002
Michelle C. Barbeau, Brooke A. Brown, Sara J. Adair, Todd W. Bauer, Matthew J. Lazzara
Epithelial-mesenchymal transition (EMT) occurs heterogeneously among carcinoma cells to promote chemoresistance. Identifying the signaling pathways involved will nominate drug combinations to promote chemoresponse, but cell population–level studies can be misleading, and single-cell transcriptomics are limited to indirect ontology-based inferences. To understand EMT heterogeneity at a signaling protein level, we combined iterative indirect immunofluorescence imaging of pancreas cancer cells and tumors and mutual information (MI) analysis. Focusing first on mitogen-activated protein kinase pathways, MI indicated that cell-to-cell variation in ERK activity determined EMT heterogeneity in response to different growth factors and chemotherapeutics but that JNK compensated when MEK was inhibited. Population-level models could not capture these experimentally validated MI inferences. The dominant role of ERK was consistently indicated by MI even when the analysis was expanded to include seven potential EMT-regulating signaling nodes. More generally, this work provides an approach for studying multivariate signaling-phenotype relationships based on protein measurements in any setting.
{"title":"The kinase ERK plays a conserved dominant role in the heterogeneity of epithelial-mesenchymal transition in pancreatic cancer cells","authors":"Michelle C. Barbeau, Brooke A. Brown, Sara J. Adair, Todd W. Bauer, Matthew J. Lazzara","doi":"10.1126/scisignal.ads7002","DOIUrl":"10.1126/scisignal.ads7002","url":null,"abstract":"<div >Epithelial-mesenchymal transition (EMT) occurs heterogeneously among carcinoma cells to promote chemoresistance. Identifying the signaling pathways involved will nominate drug combinations to promote chemoresponse, but cell population–level studies can be misleading, and single-cell transcriptomics are limited to indirect ontology-based inferences. To understand EMT heterogeneity at a signaling protein level, we combined iterative indirect immunofluorescence imaging of pancreas cancer cells and tumors and mutual information (MI) analysis. Focusing first on mitogen-activated protein kinase pathways, MI indicated that cell-to-cell variation in ERK activity determined EMT heterogeneity in response to different growth factors and chemotherapeutics but that JNK compensated when MEK was inhibited. Population-level models could not capture these experimentally validated MI inferences. The dominant role of ERK was consistently indicated by MI even when the analysis was expanded to include seven potential EMT-regulating signaling nodes. More generally, this work provides an approach for studying multivariate signaling-phenotype relationships based on protein measurements in any setting.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 899","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-12DOI: 10.1126/scisignal.adr9131
Dhamotharan Pattarayan, Yue Wang, Zehua Wang, Sihan Li, Xiaofei Wang, Yuang Chen, Yifei Wang, Chien-Yu Chen, Avishek Bhuniya, Ghanshyam Singh Yadav, Wen Xie, Udai S. Kammula, Song Li, Min Zhang, Da Yang
Increases in retroelement-derived double-stranded RNAs (dsRNAs) in various types of cancer cells facilitate the activation of antitumor immune responses. The long noncoding RNA EPIC1 interacts with the histone methyltransferase EZH2 and contributes to tumor immune evasion. Here, we found that EPIC1 in tumor cells suppressed cytoplasmic dsRNA accumulation, type I interferon (IFN) responses, and antitumor immunity. In various cancer cell lines, knockdown of EPIC1 stimulated the production of dsRNA from retroelements and an antiviral-like type I IFN response that activated immune cells. EPIC1 inhibited the expression of LINE, SINE, and LTR retroelements that were also repressed by EZH2, suggesting a potential role for the EPIC1-EZH2 interaction in regulating dsRNA production. In a humanized mouse model, in vivo delivery of EPIC1-targeting oligonucleotides enhanced dsRNA accumulation in breast cancer xenografts, reduced tumor growth, and increased the infiltration of T cells and inflammatory macrophages into tumors. Furthermore, EPIC1 knockdown improved the therapeutic efficacy of the immunotherapy drug pembrolizumab, a PD-1 inhibitor, in the humanized mouse model. Together, our findings establish EPIC1 as a key regulator of dsRNA-mediated type I IFN responses and highlight its potential as a therapeutic target to improve the efficacy of immunotherapy.
{"title":"The lncRNA EPIC1 suppresses dsRNA-induced type I IFN signaling and is a therapeutic target to enhance TNBC response to PD-1 inhibition","authors":"Dhamotharan Pattarayan, Yue Wang, Zehua Wang, Sihan Li, Xiaofei Wang, Yuang Chen, Yifei Wang, Chien-Yu Chen, Avishek Bhuniya, Ghanshyam Singh Yadav, Wen Xie, Udai S. Kammula, Song Li, Min Zhang, Da Yang","doi":"10.1126/scisignal.adr9131","DOIUrl":"10.1126/scisignal.adr9131","url":null,"abstract":"<div >Increases in retroelement-derived double-stranded RNAs (dsRNAs) in various types of cancer cells facilitate the activation of antitumor immune responses. The long noncoding RNA EPIC1 interacts with the histone methyltransferase EZH2 and contributes to tumor immune evasion. Here, we found that EPIC1 in tumor cells suppressed cytoplasmic dsRNA accumulation, type I interferon (IFN) responses, and antitumor immunity. In various cancer cell lines, knockdown of EPIC1 stimulated the production of dsRNA from retroelements and an antiviral-like type I IFN response that activated immune cells. EPIC1 inhibited the expression of LINE, SINE, and LTR retroelements that were also repressed by EZH2, suggesting a potential role for the EPIC1-EZH2 interaction in regulating dsRNA production. In a humanized mouse model, in vivo delivery of EPIC1-targeting oligonucleotides enhanced dsRNA accumulation in breast cancer xenografts, reduced tumor growth, and increased the infiltration of T cells and inflammatory macrophages into tumors. Furthermore, EPIC1 knockdown improved the therapeutic efficacy of the immunotherapy drug pembrolizumab, a PD-1 inhibitor, in the humanized mouse model. Together, our findings establish EPIC1 as a key regulator of dsRNA-mediated type I IFN responses and highlight its potential as a therapeutic target to improve the efficacy of immunotherapy.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 899","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-05DOI: 10.1126/scisignal.ads7889
Anthony C. Restaino, Maryam Ahmadi, Tuany Eichwald, Amin Reza Nikpoor, Austin Walz, Mohammad Balood, Sebastien Talbot, Paola D. Vermeer
Small extracellular vesicles (sEVs) released from tumors recruit nociceptor neurons to the tumor bed. Here, we found that ablating these neurons in mouse models of head and neck carcinoma and melanoma reduced the infiltration of myeloid-derived suppressor cells (MDSCs). Moreover, sEV-deficient tumors failed to develop in mice lacking nociceptor neurons. We investigated the interplay between tumor-infiltrating nociceptors and immune cells in head and neck squamous cell carcinoma (HNSCC) and melanoma. Upon exposure to cancer-derived sEVs, mouse dorsal root ganglion (DRG) neurons secreted increased amounts of substance P, IL-6, and injury-associated neuronal markers. Patient-derived sEVs sensitized DRG neurons to capsaicin, implying enhanced nociceptor responsiveness. Furthermore, nociceptors cultured with sEVs induced an immunosuppressed state in CD8+ T cells. Incubation with conditioned medium from cocultures of neurons and cancer cells resulted in increased expression of markers of MDSCs and suppressive function in primary bone marrow cells, and the combination of neuron-conditioned medium and cancer sEVs promoted checkpoint receptor expression on T cells. Together, these findings reveal that nociceptor neurons facilitate CD8+ T cell exhaustion and bolster MDSC infiltration into HNSCC and melanoma. Consequently, targeting nociceptors may provide a strategy to disrupt detrimental neuroimmune cross-talk in cancer and potentiate antitumor immunity.
{"title":"Tumor-infiltrating nociceptor neurons promote immunosuppression","authors":"Anthony C. Restaino, Maryam Ahmadi, Tuany Eichwald, Amin Reza Nikpoor, Austin Walz, Mohammad Balood, Sebastien Talbot, Paola D. Vermeer","doi":"10.1126/scisignal.ads7889","DOIUrl":"10.1126/scisignal.ads7889","url":null,"abstract":"<div >Small extracellular vesicles (sEVs) released from tumors recruit nociceptor neurons to the tumor bed. Here, we found that ablating these neurons in mouse models of head and neck carcinoma and melanoma reduced the infiltration of myeloid-derived suppressor cells (MDSCs). Moreover, sEV-deficient tumors failed to develop in mice lacking nociceptor neurons. We investigated the interplay between tumor-infiltrating nociceptors and immune cells in head and neck squamous cell carcinoma (HNSCC) and melanoma. Upon exposure to cancer-derived sEVs, mouse dorsal root ganglion (DRG) neurons secreted increased amounts of substance P, IL-6, and injury-associated neuronal markers. Patient-derived sEVs sensitized DRG neurons to capsaicin, implying enhanced nociceptor responsiveness. Furthermore, nociceptors cultured with sEVs induced an immunosuppressed state in CD8<sup>+</sup> T cells. Incubation with conditioned medium from cocultures of neurons and cancer cells resulted in increased expression of markers of MDSCs and suppressive function in primary bone marrow cells, and the combination of neuron-conditioned medium and cancer sEVs promoted checkpoint receptor expression on T cells. Together, these findings reveal that nociceptor neurons facilitate CD8<sup>+</sup> T cell exhaustion and bolster MDSC infiltration into HNSCC and melanoma. Consequently, targeting nociceptors may provide a strategy to disrupt detrimental neuroimmune cross-talk in cancer and potentiate antitumor immunity.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 898","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.ads7889","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144782960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-05DOI: 10.1126/scisignal.ady6769
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.
{"title":"Tumor-derived small extracellular vesicles reprogram sensory nerves to drive immunosuppression in the tumor microenvironment","authors":"Leah Boyd, Jeremy C. Borniger","doi":"10.1126/scisignal.ady6769","DOIUrl":"10.1126/scisignal.ady6769","url":null,"abstract":"<div >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 <i>Science Signaling</i>, Restaino <i>et al.</i> 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.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 898","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144782959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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