Pub Date : 2025-12-09DOI: 10.1126/scisignal.ado2768
Akashdip Singh, Saskia V. Vijver, Hajar Aglmous-Talibi, Nebojsa Jukic, Peirong Chen, Suzanne Crawley, Kalyani Mondal, Jing Zhou, Christian Niederauer, Zimple Matharu, Betty Li, Bin Fan, Michiel van der Vlist, Daniel D. Kaplan, Lee B. Rivera, James Sissons, Jonathan Sitrin, Kristina A. Ganzinger, M. Inês Pascoal Ramos, Linde Meyaard
LAIR-1 is an inhibitory receptor on immune cells that recognizes collagens and collagen domain–containing proteins. The high abundance of both LAIR-1 and its ligands suggests tight regulation of this interaction. MARCO is a scavenger receptor with a collagen-like domain that is highly expressed on immunosuppressive macrophages. Here, we identified MARCO as a ligand for LAIR-1. MARCO interacted with LAIR-1 in trans and induced inhibitory signaling by LAIR-1 in human natural killer (NK) cells. MARCO and LAIR-1 were coexpressed by human macrophages in tumors and after stimulation of monocyte-derived macrophages with the cytokine interleukin-10 (IL-10) in vitro. Single-molecule fluorescence microscopy demonstrated that MARCO and LAIR-1 interacted in cis on THP-1 macrophages. Whereas the interaction did not affect the scavenger function of MARCO on human macrophages, it reduced both LAIR-1 binding and the LAIR-1 signaling response to collagen. LAIR-1–mediated inhibitory function was increased after CRISPR-Cas9–mediated knockout of MARCO in IL-10–polarized primary human monocyte-derived macrophages. Our results identify MARCO as a regulator of LAIR-1 signaling and suggest that the induction of MARCO on immunosuppressive macrophages could enhance their function by releasing LAIR-1–mediated inhibition.
{"title":"The scavenger receptor MARCO is a ligand for the immune inhibitory receptor LAIR-1 and regulates its function in cis","authors":"Akashdip Singh, Saskia V. Vijver, Hajar Aglmous-Talibi, Nebojsa Jukic, Peirong Chen, Suzanne Crawley, Kalyani Mondal, Jing Zhou, Christian Niederauer, Zimple Matharu, Betty Li, Bin Fan, Michiel van der Vlist, Daniel D. Kaplan, Lee B. Rivera, James Sissons, Jonathan Sitrin, Kristina A. Ganzinger, M. Inês Pascoal Ramos, Linde Meyaard","doi":"10.1126/scisignal.ado2768","DOIUrl":"10.1126/scisignal.ado2768","url":null,"abstract":"<div >LAIR-1 is an inhibitory receptor on immune cells that recognizes collagens and collagen domain–containing proteins. The high abundance of both LAIR-1 and its ligands suggests tight regulation of this interaction. MARCO is a scavenger receptor with a collagen-like domain that is highly expressed on immunosuppressive macrophages. Here, we identified MARCO as a ligand for LAIR-1. MARCO interacted with LAIR-1 in trans and induced inhibitory signaling by LAIR-1 in human natural killer (NK) cells. MARCO and LAIR-1 were coexpressed by human macrophages in tumors and after stimulation of monocyte-derived macrophages with the cytokine interleukin-10 (IL-10) in vitro. Single-molecule fluorescence microscopy demonstrated that MARCO and LAIR-1 interacted in cis on THP-1 macrophages. Whereas the interaction did not affect the scavenger function of MARCO on human macrophages, it reduced both LAIR-1 binding and the LAIR-1 signaling response to collagen. LAIR-1–mediated inhibitory function was increased after CRISPR-Cas9–mediated knockout of MARCO in IL-10–polarized primary human monocyte-derived macrophages. Our results identify MARCO as a regulator of LAIR-1 signaling and suggest that the induction of MARCO on immunosuppressive macrophages could enhance their function by releasing LAIR-1–mediated inhibition.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 916","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145706674","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 : 2025-12-09DOI: 10.1126/scisignal.adp7760
Kwun Nok Mimi Man, Sarah L. S. Rougé, Ruben A. Berumen, Ariel A. Jacobi, Justin C. Weiner, Shawheen Y. Naderi, Kyle E. Ireton, Zoila M. Estrada-Tobar, Zhuoer Zeng, Joseph M. Martinez, Yang K. Xiang, Madeline Nieves-Cintrón, Manuel F. Navedo, Peter Bartels, Mary C. Horne, Johannes W. Hell
Dopamine drives the neuronal activity and synaptic plasticity required for various forms of learning. It supports short-term working memory through activation of the D1-like dopamine receptors D1 and D5. Here, we found that the L-type Ca2+ channel CaV1.2 was a critical mediator of D1/5 signaling in hippocampal pyramidal neurons. In cultured mouse hippocampal neurons, a D1/5 agonist augmented currents through CaV1.2 in the soma and Ca2+ influx in the dendrites. This effect was mediated through the second messenger cAMP and cAMP-dependent protein kinase (PKA), which phosphorylated the CaV1.2 α1 subunit at Ser1928. CaV1.2 and D5 colocalized, suggesting that this signaling was spatially restricted. In mice, D1/5 agonism facilitated spatial working memory in wild-type but not litter-matched CaV1.2 α1 S1928A knockin animals. These findings identify CaV1.2 as a key D1/5 signaling effector that supports dopamine-driven executive functions in cognition.
{"title":"Stimulation of Ca2+ channel CaV1.2 activity by dopamine signaling augments spatial working memory","authors":"Kwun Nok Mimi Man, Sarah L. S. Rougé, Ruben A. Berumen, Ariel A. Jacobi, Justin C. Weiner, Shawheen Y. Naderi, Kyle E. Ireton, Zoila M. Estrada-Tobar, Zhuoer Zeng, Joseph M. Martinez, Yang K. Xiang, Madeline Nieves-Cintrón, Manuel F. Navedo, Peter Bartels, Mary C. Horne, Johannes W. Hell","doi":"10.1126/scisignal.adp7760","DOIUrl":"10.1126/scisignal.adp7760","url":null,"abstract":"<div >Dopamine drives the neuronal activity and synaptic plasticity required for various forms of learning. It supports short-term working memory through activation of the D<sub>1</sub>-like dopamine receptors D<sub>1</sub> and D<sub>5</sub>. Here, we found that the L-type Ca<sup>2+</sup> channel Ca<sub>V</sub>1.2 was a critical mediator of D<sub>1/5</sub> signaling in hippocampal pyramidal neurons. In cultured mouse hippocampal neurons, a D<sub>1/5</sub> agonist augmented currents through Ca<sub>V</sub>1.2 in the soma and Ca<sup>2+</sup> influx in the dendrites. This effect was mediated through the second messenger cAMP and cAMP-dependent protein kinase (PKA), which phosphorylated the Ca<sub>V</sub>1.2 α<sub>1</sub> subunit at Ser<sup>1928</sup>. Ca<sub>V</sub>1.2 and D<sub>5</sub> colocalized, suggesting that this signaling was spatially restricted. In mice, D<sub>1/5</sub> agonism facilitated spatial working memory in wild-type but not litter-matched Ca<sub>V</sub>1.2 α<sub>1</sub> S1928A knockin animals. These findings identify Ca<sub>V</sub>1.2 as a key D<sub>1/5</sub> signaling effector that supports dopamine-driven executive functions in cognition.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 916","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adp7760","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145706673","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 : 2025-12-02DOI: 10.1126/scisignal.adw2270
Weiwei Zhang, Nilay Kumar, Jessica R. Helwig, Alexis Hoerter, Anjali S. Iyer-Pascuzzi, David M. Umulis, Elsje Pienaar, Christopher J. Staiger
Cytosolic calcium ion (Ca2+) signatures with specific spatiotemporal patterns play crucial roles in plant responses to biotic and abiotic stresses. The perception of microbe- or damage-associated molecular patterns (MAMPs or DAMPs, respectively) initiates cytosolic Ca2+ fluxes that are essential for the induction and spread of pattern-triggered immunity, the first line of plant defense against pathogens, at the cellular, organ, and systemic levels. Here, we quantitatively assessed Ca2+ signatures at the single-cell level, as well as the local traveling Ca2+ waves induced by uniform MAMP or DAMP treatment of Arabidopsis thaliana cotyledons. MAMPs and DAMPs induced distinct local spatiotemporal Ca2+ responses in epidermal pavement cells, with traveling waves of Ca2+ consistently initiated from a randomly distributed subset of cells and spreading in an approximately radial pattern. These local traveling waves propagated at a slow but constant speed of ~1 micrometer per second and spread to a limited number of neighboring cells. In contrast, wound-induced traveling waves of Ca2+, which are propagated by the diffusion of molecules that activate Ca2+ channels, displayed a diffusion-like decay pattern that moved rapidly away from the wounded cell but with diminishing speed over time and distance. Mathematical modeling supported a Ca2+-induced Ca2+ release mechanism that recapitulated the constant wave speed induced by MAMPs. These findings contribute to a deeper understanding of plant defense–related Ca2+ signaling mechanisms, as well as how defense responses are spatially restricted in tissues.
{"title":"Local traveling waves of cytosolic Ca2+ elicited by defense signals or wounding are propagated by distinct mechanisms in Arabidopsis","authors":"Weiwei Zhang, Nilay Kumar, Jessica R. Helwig, Alexis Hoerter, Anjali S. Iyer-Pascuzzi, David M. Umulis, Elsje Pienaar, Christopher J. Staiger","doi":"10.1126/scisignal.adw2270","DOIUrl":"10.1126/scisignal.adw2270","url":null,"abstract":"<div >Cytosolic calcium ion (Ca<sup>2+</sup>) signatures with specific spatiotemporal patterns play crucial roles in plant responses to biotic and abiotic stresses. The perception of microbe- or damage-associated molecular patterns (MAMPs or DAMPs, respectively) initiates cytosolic Ca<sup>2+</sup> fluxes that are essential for the induction and spread of pattern-triggered immunity, the first line of plant defense against pathogens, at the cellular, organ, and systemic levels. Here, we quantitatively assessed Ca<sup>2+</sup> signatures at the single-cell level, as well as the local traveling Ca<sup>2+</sup> waves induced by uniform MAMP or DAMP treatment of <i>Arabidopsis thaliana</i> cotyledons. MAMPs and DAMPs induced distinct local spatiotemporal Ca<sup>2+</sup> responses in epidermal pavement cells, with traveling waves of Ca<sup>2+</sup> consistently initiated from a randomly distributed subset of cells and spreading in an approximately radial pattern. These local traveling waves propagated at a slow but constant speed of ~1 micrometer per second and spread to a limited number of neighboring cells. In contrast, wound-induced traveling waves of Ca<sup>2+</sup>, which are propagated by the diffusion of molecules that activate Ca<sup>2+</sup> channels, displayed a diffusion-like decay pattern that moved rapidly away from the wounded cell but with diminishing speed over time and distance. Mathematical modeling supported a Ca<sup>2+</sup>-induced Ca<sup>2+</sup> release mechanism that recapitulated the constant wave speed induced by MAMPs. These findings contribute to a deeper understanding of plant defense–related Ca<sup>2+</sup> signaling mechanisms, as well as how defense responses are spatially restricted in tissues.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 915","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145652869","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 : 2025-12-02DOI: 10.1126/scisignal.adt8890
Marlene Fritsche, Gaia Picozzi, Tomas Nyman, Hugo Zeberg, Richard Ågren
G protein–coupled receptors (GPCRs) play key roles in neurodevelopment by regulating excitatory and inhibitory neuronal pathways. The G protein subunit Gαi1 is a downstream effector of inhibitory GPCR signaling, and the gene encoding it (GNAI1) is abundantly expressed in the brain. Rare GNAI1 variants are linked to a severe neurodevelopmental disorder called GNAI1 syndrome, which is characterized by intellectual disability, a range of movement issues, and epilepsy. Here, we investigated the effect of five GNAI1 syndrome–associated missense variants on GPCR signaling. Predictions based on genetic biobank data and in silico modeling suggested that these variants were pathogenic. Compared with the wild-type protein, four Gαi1 variants (T48K, T48I, C224Y, and V332E) showed marked increases in dopamine potency at the dopamine D2 receptor (D2R) and increased constitutive G protein activity when expressed in Xenopus laevis oocytes. By contrast, the Gαi1 G40C variant was unresponsive to D2R activation. All Gαi1 variants displayed reduced GTP-γ-S binding rates and undetectable GTP hydrolysis, except for the T48I variant, which showed more rapid binding and hydrolysis. Thus, four GNAI1 syndrome variants caused a net gain-of-function effect on D2R signaling, and all studied variants disrupted GTP exchange. These biochemical effects may underlie GNAI1 syndrome, and GNAI1 mutations should therefore be considered when screening for rare neurodevelopmental disorders.
{"title":"GNAI1 missense mutations associated with a neurodevelopmental syndrome modify Gαi1 function","authors":"Marlene Fritsche, Gaia Picozzi, Tomas Nyman, Hugo Zeberg, Richard Ågren","doi":"10.1126/scisignal.adt8890","DOIUrl":"10.1126/scisignal.adt8890","url":null,"abstract":"<div >G protein–coupled receptors (GPCRs) play key roles in neurodevelopment by regulating excitatory and inhibitory neuronal pathways. The G protein subunit Gα<sub>i1</sub> is a downstream effector of inhibitory GPCR signaling, and the gene encoding it (<i>GNAI1</i>) is abundantly expressed in the brain. Rare <i>GNAI1</i> variants are linked to a severe neurodevelopmental disorder called <i>GNAI1</i> syndrome, which is characterized by intellectual disability, a range of movement issues, and epilepsy. Here, we investigated the effect of five <i>GNAI1</i> syndrome–associated missense variants on GPCR signaling. Predictions based on genetic biobank data and in silico modeling suggested that these variants were pathogenic. Compared with the wild-type protein, four Gα<sub>i1</sub> variants (T48K, T48I, C224Y, and V332E) showed marked increases in dopamine potency at the dopamine D2 receptor (D2R) and increased constitutive G protein activity when expressed in <i>Xenopus laevis</i> oocytes. By contrast, the Gα<sub>i1</sub> G40C variant was unresponsive to D2R activation. All Gα<sub>i1</sub> variants displayed reduced GTP-γ-S binding rates and undetectable GTP hydrolysis, except for the T48I variant, which showed more rapid binding and hydrolysis. Thus, four <i>GNAI1</i> syndrome variants caused a net gain-of-function effect on D2R signaling, and all studied variants disrupted GTP exchange. These biochemical effects may underlie <i>GNAI1</i> syndrome, and <i>GNAI1</i> mutations should therefore be considered when screening for rare neurodevelopmental disorders.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 915","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145652870","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 : 2025-12-02DOI: 10.1126/scisignal.aeb7956
Simon Gilroy
Waves of Ca2+ signals rapidly propagate throughout a plant to help integrate responses to stimuli as diverse as wounding, heat stress, and pathogen attack. In this issue of Science Signaling, Zhang et al. show that bacterial elicitors and physical injury likely use different molecular mechanisms to produce distinct patterns of Ca2+ waves, shedding light on how such a universal signal leads to stimulus-specific responses.
{"title":"Waving hello to pathogens: The dynamics of the spread of plant MAMP-triggered Ca2+ signaling","authors":"Simon Gilroy","doi":"10.1126/scisignal.aeb7956","DOIUrl":"10.1126/scisignal.aeb7956","url":null,"abstract":"<div >Waves of Ca<sup>2+</sup> signals rapidly propagate throughout a plant to help integrate responses to stimuli as diverse as wounding, heat stress, and pathogen attack. In this issue of <i>Science Signaling</i>, Zhang <i>et al</i>. show that bacterial elicitors and physical injury likely use different molecular mechanisms to produce distinct patterns of Ca<sup>2+</sup> waves, shedding light on how such a universal signal leads to stimulus-specific responses.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 915","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145652868","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 : 2025-11-25DOI: 10.1126/scisignal.adv0415
Chance C. Sine, Lotte P. Watts, Brianna Fernandez, Nasreen Marikar, Jianxin Wang, Erik S. Knudsen, Agnieszka K. Witkiewicz, Sabrina L. Spencer
Blocking the cell cycle is a promising avenue for cancer therapy, with cyclin-dependent kinase 2 (CDK2) emerging as a key target. However, in multiple cell types, the activities of CDK4 and CDK6 (CDK4/6) compensate for CDK2 inhibition and sustain tumor cell proliferation, enabling CDK2 reactivation. Thus, we hypothesized that sensitivity to CDK2 inhibition is linked to the absence of this CDK4/6-mediated compensatory mechanism. We found that cyclin E1–driven ovarian cancers often coexpressed the tumor suppressor p16, which inhibited CDK4/6 signaling. Single-cell time-lapse imaging showed that high abundance of p16 conferred increased sensitivity to CDK2 inhibitors, whereas depletion of p16 rendered cells more resistant to CDK2 inhibition through CDK4/6-dependent compensation. Concordantly, acquired resistance to CDK2 inhibitors correlated with reduced p16 and increased cyclin D1 protein abundance. Multiplexed immunofluorescence of 225 ovarian tumors from patients revealed that 18% of the tumors had high cyclin E1 and p16 expression. Thus, p16 may be a useful biomarker for identifying patients most likely to benefit from CDK2 inhibitors.
{"title":"p16 expression confers sensitivity to CDK2 inhibitors in cyclin E1–driven ovarian cancers","authors":"Chance C. Sine, Lotte P. Watts, Brianna Fernandez, Nasreen Marikar, Jianxin Wang, Erik S. Knudsen, Agnieszka K. Witkiewicz, Sabrina L. Spencer","doi":"10.1126/scisignal.adv0415","DOIUrl":"10.1126/scisignal.adv0415","url":null,"abstract":"<div >Blocking the cell cycle is a promising avenue for cancer therapy, with cyclin-dependent kinase 2 (CDK2) emerging as a key target. However, in multiple cell types, the activities of CDK4 and CDK6 (CDK4/6) compensate for CDK2 inhibition and sustain tumor cell proliferation, enabling CDK2 reactivation. Thus, we hypothesized that sensitivity to CDK2 inhibition is linked to the absence of this CDK4/6-mediated compensatory mechanism. We found that cyclin E1–driven ovarian cancers often coexpressed the tumor suppressor p16, which inhibited CDK4/6 signaling. Single-cell time-lapse imaging showed that high abundance of p16 conferred increased sensitivity to CDK2 inhibitors, whereas depletion of p16 rendered cells more resistant to CDK2 inhibition through CDK4/6-dependent compensation. Concordantly, acquired resistance to CDK2 inhibitors correlated with reduced p16 and increased cyclin D1 protein abundance. Multiplexed immunofluorescence of 225 ovarian tumors from patients revealed that 18% of the tumors had high cyclin E1 and p16 expression. Thus, p16 may be a useful biomarker for identifying patients most likely to benefit from CDK2 inhibitors.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 914","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adv0415","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145595398","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 : 2025-11-25DOI: 10.1126/scisignal.aee0649
Wei Wong
Stem cells in hair follicles can be activated after skin injury by fatty acids released from adipocytes.
皮肤损伤后毛囊干细胞可被脂肪细胞释放的脂肪酸激活。
{"title":"The fatty acid method for regrowing hair","authors":"Wei Wong","doi":"10.1126/scisignal.aee0649","DOIUrl":"10.1126/scisignal.aee0649","url":null,"abstract":"<div >Stem cells in hair follicles can be activated after skin injury by fatty acids released from adipocytes.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 914","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145595397","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 : 2025-11-25DOI: 10.1126/scisignal.aea2788
Brianna R. Daley, Patricia L. Theard, Jacob M. Hughes, Bridget A. Finniff, Marco H. Hofmann, Kaja Kostyrko, Robyn L. Schenk, Heidi M. Vieira, James W. Askew, Robert E. Lewis, Robert L. Kortum
Osimertinib is the mainstay of therapy for patients with non–small cell lung cancer (NSCLC) driven by the receptor tyrosine kinase (RTK) EGFR. In most patients, however, therapeutic pressure promotes RTK-dependent mechanisms that support tumor cell survival and the emergence of osimertinib resistance. Here, we found that inhibiting the proximal RTK signaling intermediate SOS1 promoted continued osimertinib efficacy in sensitive cells and restored sensitivity in cells with acquired resistance. In three-dimensional spheroid cultures of naïve NSCLC cells, SOS1 inhibition enhanced osimertinib potency by limiting the reactivation of RTK-dependent adaptive Ras effectors. SOS1 inhibition resensitized drug-tolerant persister cells to osimertinib, and knockout or inhibition of SOS1 reduced the frequency of tumor-initiating cells to curb spheroid growth in situ and tumorigenesis in vivo. SOS1 inhibition further limited the development of acquired osimertinib resistance and resensitized resistant cells to osimertinib. In mice, tumors regressed nearly completely when treated with either osimertinib or a combination of osimertinib and a SOS1 inhibitor, with the combination providing a slightly greater effect. However, only the combination delayed tumor regrowth after treatment removal. Our data provide a mechanistic rationale for the clinical investigation of combining SOS1 inhibitors with osimertinib to achieve more durable responses and suppress resistance in NSCLC.
{"title":"SOS1 inhibition suppresses the emergence of osimertinib resistance to generate a durable response in EGFR-mutant lung cancer","authors":"Brianna R. Daley, Patricia L. Theard, Jacob M. Hughes, Bridget A. Finniff, Marco H. Hofmann, Kaja Kostyrko, Robyn L. Schenk, Heidi M. Vieira, James W. Askew, Robert E. Lewis, Robert L. Kortum","doi":"10.1126/scisignal.aea2788","DOIUrl":"10.1126/scisignal.aea2788","url":null,"abstract":"<div >Osimertinib is the mainstay of therapy for patients with non–small cell lung cancer (NSCLC) driven by the receptor tyrosine kinase (RTK) EGFR. In most patients, however, therapeutic pressure promotes RTK-dependent mechanisms that support tumor cell survival and the emergence of osimertinib resistance. Here, we found that inhibiting the proximal RTK signaling intermediate SOS1 promoted continued osimertinib efficacy in sensitive cells and restored sensitivity in cells with acquired resistance. In three-dimensional spheroid cultures of naïve NSCLC cells, SOS1 inhibition enhanced osimertinib potency by limiting the reactivation of RTK-dependent adaptive Ras effectors. SOS1 inhibition resensitized drug-tolerant persister cells to osimertinib, and knockout or inhibition of SOS1 reduced the frequency of tumor-initiating cells to curb spheroid growth in situ and tumorigenesis in vivo. SOS1 inhibition further limited the development of acquired osimertinib resistance and resensitized resistant cells to osimertinib. In mice, tumors regressed nearly completely when treated with either osimertinib or a combination of osimertinib and a SOS1 inhibitor, with the combination providing a slightly greater effect. However, only the combination delayed tumor regrowth after treatment removal. Our data provide a mechanistic rationale for the clinical investigation of combining SOS1 inhibitors with osimertinib to achieve more durable responses and suppress resistance in NSCLC.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 914","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145595399","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 : 2025-11-18DOI: 10.1126/scisignal.ady0398
Davide Cinat, Ryan van der Wal, Mirjam Baanstra, Abel Soto-Gamez, Rufina Maturi, Anne L. Jellema-de Bruin, Uilke Brouwer, Marc-Jan van Goethem, Marcel A. T. M. van Vugt, Lara Barazzuol, Rob P. Coppes
The goal of radiotherapy in cancer treatment is to maximize DNA damage in tumors while minimizing harm to surrounding healthy tissues, especially to stem and progenitor cells essential for tissue regeneration and organ function. Here, we investigated the molecular responses to photon and proton irradiation, two key modalities in head and neck cancer treatment. Multiomics and in vitro analyses revealed that both photon and proton irradiation of mouse salivary gland organoids induced similar early responses, including DNA damage, micronuclei formation, increased amounts of the cytosolic DNA sensor cGAS, and type I interferon (IFN-I) signaling. In addition, both types of radiation induced comparable increases in the release of mitochondrial DNA (mtDNA) into the cytoplasm and stimulated the production of ZBP1, a cytosolic nucleic acid sensor involved in mtDNA recognition. However, proton irradiation resulted in a more pronounced loss of heterochromatin regulators and derepression of transposable elements at later times after irradiation, which was accompanied by increased accumulation of intracellular double-stranded RNA (dsRNA) and an enhanced RIG-I–mediated IFN-I response. Genetic and pharmacological modulation demonstrated its critical role for IFN-I signaling in enhancing salivary gland stem and progenitor cell activity after irradiation in vitro and in vivo. Our findings reveal more pronounced molecular changes after proton irradiation as compared with photon irradiation and uncover a proregenerative role of IFN-I signaling in the salivary gland, suggesting this pathway as a promising therapeutic target to mitigate radiation-induced side effects.
{"title":"IFN-I signaling enhances salivary gland stem and progenitor cell activity after irradiation","authors":"Davide Cinat, Ryan van der Wal, Mirjam Baanstra, Abel Soto-Gamez, Rufina Maturi, Anne L. Jellema-de Bruin, Uilke Brouwer, Marc-Jan van Goethem, Marcel A. T. M. van Vugt, Lara Barazzuol, Rob P. Coppes","doi":"10.1126/scisignal.ady0398","DOIUrl":"10.1126/scisignal.ady0398","url":null,"abstract":"<div >The goal of radiotherapy in cancer treatment is to maximize DNA damage in tumors while minimizing harm to surrounding healthy tissues, especially to stem and progenitor cells essential for tissue regeneration and organ function. Here, we investigated the molecular responses to photon and proton irradiation, two key modalities in head and neck cancer treatment. Multiomics and in vitro analyses revealed that both photon and proton irradiation of mouse salivary gland organoids induced similar early responses, including DNA damage, micronuclei formation, increased amounts of the cytosolic DNA sensor cGAS, and type I interferon (IFN-I) signaling. In addition, both types of radiation induced comparable increases in the release of mitochondrial DNA (mtDNA) into the cytoplasm and stimulated the production of ZBP1, a cytosolic nucleic acid sensor involved in mtDNA recognition. However, proton irradiation resulted in a more pronounced loss of heterochromatin regulators and derepression of transposable elements at later times after irradiation, which was accompanied by increased accumulation of intracellular double-stranded RNA (dsRNA) and an enhanced RIG-I–mediated IFN-I response. Genetic and pharmacological modulation demonstrated its critical role for IFN-I signaling in enhancing salivary gland stem and progenitor cell activity after irradiation in vitro and in vivo. Our findings reveal more pronounced molecular changes after proton irradiation as compared with photon irradiation and uncover a proregenerative role of IFN-I signaling in the salivary gland, suggesting this pathway as a promising therapeutic target to mitigate radiation-induced side effects.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 913","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145538107","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 : 2025-11-18DOI: 10.1126/scisignal.aeb6151
Yoshiaki Sato, Jian Yu
Innate immune signaling is important for tissue regeneration. In this issue of Science Signaling, Cinat et al. report that a cell-intrinsic type I interferon (IFN-I) response drives salivary gland organoid regeneration after radiation and that proton irradiation induces a stronger regenerative response than photon irradiation because it amplifies the IFN-I response.
{"title":"Jump-starting IFN-I responses and epithelial regeneration","authors":"Yoshiaki Sato, Jian Yu","doi":"10.1126/scisignal.aeb6151","DOIUrl":"10.1126/scisignal.aeb6151","url":null,"abstract":"<div >Innate immune signaling is important for tissue regeneration. In this issue of <i>Science Signaling</i>, Cinat <i>et al</i>. report that a cell-intrinsic type I interferon (IFN-I) response drives salivary gland organoid regeneration after radiation and that proton irradiation induces a stronger regenerative response than photon irradiation because it amplifies the IFN-I response.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 913","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145538108","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号