Pub Date : 2025-02-12DOI: 10.1126/scitranslmed.adq3110
Jose L. Montoya Mira, Arnaud Quentel, Ranish K. Patel, Dove Keith, Megan Sousa, Jessica Minnier, Benjamin R. Kingston, Larry David, Sadik C. Esener, Rosalie C. Sears, Charles D. Lopez, Brett C. Sheppard, Utkan Demirci, Melissa H. Wong, Jared M. Fischer
Pancreatic ductal adenocarcinoma (PDAC) is among the top causes of cancer-related death. Patients are frequently diagnosed in the more advanced stages when effective treatment options are limited; however, earlier detection of PDAC by liquid biopsy may expand treatment options and improve survival outcomes. Here, we developed a noninvasive detection assay for PDAC based on serum protease activity to leverage the increase in cancer-associated protease activity in the peripheral blood of patients with PDAC. We screened a series of protease-cleavable peptide probes for the discrimination of PDAC samples versus healthy controls and noncancerous pancreatic disease. We identified a single MMP-sensitive probe, which could distinguish PDAC from controls with 79 ± 6% accuracy. We further developed this probe into a rapid magnetic nanosensor assay, termed PAC-MANN, that measures serum protease cleavage of a target-probe nanosensor with a simple fluorescent readout. In a longitudinal cohort of patients undergoing surgical removal of the primary tumor, the probe cleavage signal was reduced by 16 ± 24% after surgery. In a separate blinded retrospective study, the PAC-MANN assay identified PDAC samples with 98% specificity and 73% sensitivity across all stages and distinguished 100% of patients with noncancer pancreatic disease relative to patients with PDAC. The PAC-MANN assay combined with the clinical biomarker CA 19-9 was 85% sensitive for detection of stage I PDAC with 96% specificity. Therefore, the PAC-MANN assay is a rapid, high-throughput method that uses small blood volumes with the potential to enhance early PDAC detection, specifically among individuals at high risk of developing PDAC.
{"title":"Early detection of pancreatic cancer by a high-throughput protease-activated nanosensor assay","authors":"Jose L. Montoya Mira, Arnaud Quentel, Ranish K. Patel, Dove Keith, Megan Sousa, Jessica Minnier, Benjamin R. Kingston, Larry David, Sadik C. Esener, Rosalie C. Sears, Charles D. Lopez, Brett C. Sheppard, Utkan Demirci, Melissa H. Wong, Jared M. Fischer","doi":"10.1126/scitranslmed.adq3110","DOIUrl":"https://doi.org/10.1126/scitranslmed.adq3110","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is among the top causes of cancer-related death. Patients are frequently diagnosed in the more advanced stages when effective treatment options are limited; however, earlier detection of PDAC by liquid biopsy may expand treatment options and improve survival outcomes. Here, we developed a noninvasive detection assay for PDAC based on serum protease activity to leverage the increase in cancer-associated protease activity in the peripheral blood of patients with PDAC. We screened a series of protease-cleavable peptide probes for the discrimination of PDAC samples versus healthy controls and noncancerous pancreatic disease. We identified a single MMP-sensitive probe, which could distinguish PDAC from controls with 79 ± 6% accuracy. We further developed this probe into a rapid magnetic nanosensor assay, termed PAC-MANN, that measures serum protease cleavage of a target-probe nanosensor with a simple fluorescent readout. In a longitudinal cohort of patients undergoing surgical removal of the primary tumor, the probe cleavage signal was reduced by 16 ± 24% after surgery. In a separate blinded retrospective study, the PAC-MANN assay identified PDAC samples with 98% specificity and 73% sensitivity across all stages and distinguished 100% of patients with noncancer pancreatic disease relative to patients with PDAC. The PAC-MANN assay combined with the clinical biomarker CA 19-9 was 85% sensitive for detection of stage I PDAC with 96% specificity. Therefore, the PAC-MANN assay is a rapid, high-throughput method that uses small blood volumes with the potential to enhance early PDAC detection, specifically among individuals at high risk of developing PDAC.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"13 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marco De Giorgi, So Hyun Park, Adam Castoreno, Mingming Cao, Ayrea Hurley, Lavanya Saxena, Marcel A. Chuecos, Christopher J. Walkey, Alexandria M. Doerfler, Mia N. Furgurson, M. Cecilia Ljungberg, Kalyani R. Patel, Sarah Hyde, Tyler Chickering, Stephanie Lefebvre, Kelly Wassarman, Patrick Miller, June Qin, Mark K. Schlegel, Ivan Zlatev, Jun Han, Christine Beeton, Rich Gang Li, Jong Kim, James F. Martin, Karl-Dimiter Bissig, Vasant Jadhav, Gang Bao, William R. Lagor
Homology-directed repair (HDR)–based genome editing is an approach that could permanently correct a broad range of genetic diseases. However, its utility is limited by inefficient and imprecise DNA repair mechanisms in terminally differentiated tissues. Here, we tested Repair Drive, a platform technology for selectively expanding HDR-corrected hepatocytes in adult mice in vivo. Repair Drive involves transient conditioning of the liver by knocking down an essential gene, fumarylacetoacetate hydrolase (Fah), and delivering an untargetable version of the essential gene in cis with a therapeutic transgene. We show that Repair Drive increased the percentage of correctly targeted hepatocytes in healthy wild-type mice up to 25%, which resulted in a fivefold increased expression of a therapeutic transgene, human factor IX (FIX). Repair Drive was well tolerated and did not induce toxicity or tumorigenesis during a 1-year follow-up. This approach may broaden the range of liver diseases that can be treated with somatic genome editing.
{"title":"In vivo expansion of gene-targeted hepatocytes through transient inhibition of an essential gene","authors":"Marco De Giorgi, So Hyun Park, Adam Castoreno, Mingming Cao, Ayrea Hurley, Lavanya Saxena, Marcel A. Chuecos, Christopher J. Walkey, Alexandria M. Doerfler, Mia N. Furgurson, M. Cecilia Ljungberg, Kalyani R. Patel, Sarah Hyde, Tyler Chickering, Stephanie Lefebvre, Kelly Wassarman, Patrick Miller, June Qin, Mark K. Schlegel, Ivan Zlatev, Jun Han, Christine Beeton, Rich Gang Li, Jong Kim, James F. Martin, Karl-Dimiter Bissig, Vasant Jadhav, Gang Bao, William R. Lagor","doi":"","DOIUrl":"","url":null,"abstract":"<div >Homology-directed repair (HDR)–based genome editing is an approach that could permanently correct a broad range of genetic diseases. However, its utility is limited by inefficient and imprecise DNA repair mechanisms in terminally differentiated tissues. Here, we tested Repair Drive, a platform technology for selectively expanding HDR-corrected hepatocytes in adult mice in vivo. Repair Drive involves transient conditioning of the liver by knocking down an essential gene, <i>fumarylacetoacetate hydrolase</i> (<i>Fah</i>), and delivering an untargetable version of the essential gene in cis with a therapeutic transgene. We show that Repair Drive increased the percentage of correctly targeted hepatocytes in healthy wild-type mice up to 25%, which resulted in a fivefold increased expression of a therapeutic transgene, <i>human factor IX</i> (<i>FIX</i>). Repair Drive was well tolerated and did not induce toxicity or tumorigenesis during a 1-year follow-up. This approach may broaden the range of liver diseases that can be treated with somatic genome editing.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 785","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-12DOI: 10.1126/scitranslmed.adn3963
Aditya Rayasam, Alison Moe, Matthew Kudek, Ravi K. Shah, Cheng-Yin Yuan, James M. Miller, Mary Rau, Mollie Patton, Karolyn Wanat, Marco Colonna, Anthony E. Zamora, William R. Drobyski
Gastrointestinal (GI) tract graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation and is attributable to dysregulation that occurs between the effector and regulatory arms of the immune system. Whereas regulatory T cells have a primary role in counterbalancing GVHD-induced inflammation, identifying and harnessing other pathways that promote immune tolerance remain major goals in this disease. Herein, we identified interleukin-34 (IL-34) as an intestinal epithelium–derived cytokine that was able to mitigate the severity of GVHD within the GI tract. Specifically, we observed that the absence of recipient IL-34 production exacerbated GVHD lethality, promoted intestinal epithelial cell death, and compromised barrier integrity. Mechanistically, the absence of host IL-34 skewed donor macrophages toward a proinflammatory phenotype and augmented the accumulation of pathogenic CD4 + granulocyte-macrophage colony-stimulating factor (GM-CSF) + T cells within the colon. Conversely, the administration of recombinant IL-34 substantially reduced GVHD mortality and inflammation, which was dependent on the expression of apolipoprotein E in donor macrophages. Complementary genetic and imaging approaches in mice demonstrated that intestinal epithelial cells were the relevant source of IL-34. These results were supported by colonic biopsies from patients with GVHD, which displayed IL-34 expression in intestinal epithelial cells and apolipoprotein E in lamina propria macrophages, validating similar cellular localization in humans. These studies indicate that IL-34 acts as a tissue-intrinsic cytokine that regulates GVHD severity in the GI tract and could serve as a potential therapeutic target for amelioration of this disease.
{"title":"Intestinal epithelium–derived IL-34 reprograms macrophages to mitigate gastrointestinal tract graft-versus-host disease","authors":"Aditya Rayasam, Alison Moe, Matthew Kudek, Ravi K. Shah, Cheng-Yin Yuan, James M. Miller, Mary Rau, Mollie Patton, Karolyn Wanat, Marco Colonna, Anthony E. Zamora, William R. Drobyski","doi":"10.1126/scitranslmed.adn3963","DOIUrl":"https://doi.org/10.1126/scitranslmed.adn3963","url":null,"abstract":"Gastrointestinal (GI) tract graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation and is attributable to dysregulation that occurs between the effector and regulatory arms of the immune system. Whereas regulatory T cells have a primary role in counterbalancing GVHD-induced inflammation, identifying and harnessing other pathways that promote immune tolerance remain major goals in this disease. Herein, we identified interleukin-34 (IL-34) as an intestinal epithelium–derived cytokine that was able to mitigate the severity of GVHD within the GI tract. Specifically, we observed that the absence of recipient IL-34 production exacerbated GVHD lethality, promoted intestinal epithelial cell death, and compromised barrier integrity. Mechanistically, the absence of host IL-34 skewed donor macrophages toward a proinflammatory phenotype and augmented the accumulation of pathogenic CD4 <jats:sup>+</jats:sup> granulocyte-macrophage colony-stimulating factor (GM-CSF) <jats:sup>+</jats:sup> T cells within the colon. Conversely, the administration of recombinant IL-34 substantially reduced GVHD mortality and inflammation, which was dependent on the expression of apolipoprotein E in donor macrophages. Complementary genetic and imaging approaches in mice demonstrated that intestinal epithelial cells were the relevant source of IL-34. These results were supported by colonic biopsies from patients with GVHD, which displayed IL-34 expression in intestinal epithelial cells and apolipoprotein E in lamina propria macrophages, validating similar cellular localization in humans. These studies indicate that IL-34 acts as a tissue-intrinsic cytokine that regulates GVHD severity in the GI tract and could serve as a potential therapeutic target for amelioration of this disease.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Immune checkpoint blockade therapy has been successfully applied in clinical settings as a standard therapy for many cancer types, but its clinical efficacy is restricted to patients with immunologically hot tumors. Various strategies to modify the tumor microenvironment (TME), such as Toll-like receptor (TLR) agonists that can stimulate innate immunity, have been explored but have not been successful. Here, we show a mechanism of acquired resistance to combination treatment consisting of an agonist for multiple TLRs, OK-432 (Picibanil), and programmed cell death protein 1 (PD-1) blockade. Adding the TLR agonist failed to convert the TME from immunogenically cold to hot and did not augment antitumor immunity, particularly CD8+ T cell responses, in multiple animal models. The failure was attributed to the coactivation of innate suppressive cells, such as polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) expressing CXCR2, through high CXCL1 production by macrophages in the TME upon OK-432 treatment. A triple combination treatment with OK-432, PD-1 blockade, and a CXCR2 neutralizing antibody overcame the resistance induced by PMN-MDSCs, resulting in a stronger antitumor effect than that of any dual combinations or single treatments. The accumulation of PMN-MDSCs was similarly observed in the pleural effusions of patients with lung cancer after OK-432 administration. We propose that successful combination cancer immunotherapy intended to stimulate innate antitumor immunity requires modulation of unwanted activation of innate immune suppressive cells, including PMN-MDSCs.
{"title":"Coactivation of innate immune suppressive cells induces acquired resistance against combined TLR agonism and PD-1 blockade","authors":"Hitomi Nishinakamura, Sayoko Shinya, Takuma Irie, Shugo Sakihama, Takeo Naito, Keisuke Watanabe, Daisuke Sugiyama, Motohiro Tamiya, Tatsuya Yoshida, Tetsunari Hase, Takao Yoshida, Kennosuke Karube, Shohei Koyama, Hiroyoshi Nishikawa","doi":"","DOIUrl":"","url":null,"abstract":"<div >Immune checkpoint blockade therapy has been successfully applied in clinical settings as a standard therapy for many cancer types, but its clinical efficacy is restricted to patients with immunologically hot tumors. Various strategies to modify the tumor microenvironment (TME), such as Toll-like receptor (TLR) agonists that can stimulate innate immunity, have been explored but have not been successful. Here, we show a mechanism of acquired resistance to combination treatment consisting of an agonist for multiple TLRs, OK-432 (Picibanil), and programmed cell death protein 1 (PD-1) blockade. Adding the TLR agonist failed to convert the TME from immunogenically cold to hot and did not augment antitumor immunity, particularly CD8<sup>+</sup> T cell responses, in multiple animal models. The failure was attributed to the coactivation of innate suppressive cells, such as polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) expressing CXCR2, through high CXCL1 production by macrophages in the TME upon OK-432 treatment. A triple combination treatment with OK-432, PD-1 blockade, and a CXCR2 neutralizing antibody overcame the resistance induced by PMN-MDSCs, resulting in a stronger antitumor effect than that of any dual combinations or single treatments. The accumulation of PMN-MDSCs was similarly observed in the pleural effusions of patients with lung cancer after OK-432 administration. We propose that successful combination cancer immunotherapy intended to stimulate innate antitumor immunity requires modulation of unwanted activation of innate immune suppressive cells, including PMN-MDSCs.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 785","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pseudomonas infection after lung transplantation induces acute intragraft lymphocytotoxicity that promotes antibody-mediated rejection in mice (Liao et al., this issue).
{"title":"No tolerance for Pseudomonas in lung transplants","authors":"Idaira M. Guerrero-Fonseca, Bryan G. Yipp","doi":"","DOIUrl":"","url":null,"abstract":"<div ><i>Pseudomonas</i> infection after lung transplantation induces acute intragraft lymphocytotoxicity that promotes antibody-mediated rejection in mice (Liao <i>et al.</i>, this issue).</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 784","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-05DOI: 10.1126/scitranslmed.adj6294
Konrad Gronke, Mytien Nguyen, Helen Fuhrmann, Noemi Santamaria de Souza, Julia Schumacher, Márcia S. Pereira, Ulrike Löschberger, Anna Brinkhege, Nathalie J. Becker, Yi Yang, Nicole Sonnert, Shana Leopold, Anjelica L. Martin, Lilly von Münchow-Klein, Cecilia Pessoa Rodrigues, Dilay Cansever, Remy Hallet, Kirsten Richter, David A. Schubert, Guillaume M. Daniel, David Dylus, Marianne Forkel, Dorothee Schwinge, Christoph Schramm, Sylvio Redanz, Kara G. Lassen, Silvio Manfredo Vieira, Luca Piali, Noah W. Palm, Christoph Bieniossek, Martin A. Kriegel
Chronic autoimmune diseases often lead to long-term sequelae and require lifelong immunosuppression because of an incomplete understanding of the triggers and drivers in genetically predisposed patients. Gut bacteria that escape the gut barrier, known as translocating gut pathobionts, have been implicated as instigators and perpetuators of extraintestinal autoimmune diseases in mice. The gut microbial contributions to autoimmunity in humans remain largely unclear, including whether specific pathological human adaptive immune responses are triggered by such pathobionts. Here, we show that the translocating pathobiont Enterococcus gallinarum can induce both human and mouse interferon-γ + T helper 17 (T H 17) differentiation and immunoglobulin G3 (IgG3) subclass switch of anti– E. gallinarum RNA antibodies, which correlated with anti-human RNA autoantibody responses in patients with systemic lupus erythematosus (SLE) and autoimmune hepatitis, two extraintestinal autoimmune diseases. E. gallinarum RNA, but not human RNA, triggered Toll-like receptor 8 (TLR8), and TLR8-mediated human monocyte activation promoted human T H 17 induction by E. gallinarum . Translocation of the pathobiont triggered increased anti-RNA autoantibody titers that correlated with renal autoimmune pathophysiology in murine gnotobiotic lupus models and with disease activity in patients with SLE. These studies elucidate cellular mechanisms of how a translocating gut pathobiont induces systemic human T cell– and B cell–dependent autoimmune responses and provide a framework for developing host- and microbiota-derived biomarkers and targeted therapies in autoimmune diseases.
{"title":"Translocating gut pathobiont Enterococcus gallinarum induces T H 17 and IgG3 anti-RNA–directed autoimmunity in mouse and human","authors":"Konrad Gronke, Mytien Nguyen, Helen Fuhrmann, Noemi Santamaria de Souza, Julia Schumacher, Márcia S. Pereira, Ulrike Löschberger, Anna Brinkhege, Nathalie J. Becker, Yi Yang, Nicole Sonnert, Shana Leopold, Anjelica L. Martin, Lilly von Münchow-Klein, Cecilia Pessoa Rodrigues, Dilay Cansever, Remy Hallet, Kirsten Richter, David A. Schubert, Guillaume M. Daniel, David Dylus, Marianne Forkel, Dorothee Schwinge, Christoph Schramm, Sylvio Redanz, Kara G. Lassen, Silvio Manfredo Vieira, Luca Piali, Noah W. Palm, Christoph Bieniossek, Martin A. Kriegel","doi":"10.1126/scitranslmed.adj6294","DOIUrl":"https://doi.org/10.1126/scitranslmed.adj6294","url":null,"abstract":"Chronic autoimmune diseases often lead to long-term sequelae and require lifelong immunosuppression because of an incomplete understanding of the triggers and drivers in genetically predisposed patients. Gut bacteria that escape the gut barrier, known as translocating gut pathobionts, have been implicated as instigators and perpetuators of extraintestinal autoimmune diseases in mice. The gut microbial contributions to autoimmunity in humans remain largely unclear, including whether specific pathological human adaptive immune responses are triggered by such pathobionts. Here, we show that the translocating pathobiont <jats:italic>Enterococcus gallinarum</jats:italic> can induce both human and mouse interferon-γ <jats:sup>+</jats:sup> T helper 17 (T <jats:sub>H</jats:sub> 17) differentiation and immunoglobulin G3 (IgG3) subclass switch of anti– <jats:italic>E. gallinarum</jats:italic> RNA antibodies, which correlated with anti-human RNA autoantibody responses in patients with systemic lupus erythematosus (SLE) and autoimmune hepatitis, two extraintestinal autoimmune diseases. <jats:italic>E. gallinarum</jats:italic> RNA, but not human RNA, triggered Toll-like receptor 8 (TLR8), and TLR8-mediated human monocyte activation promoted human T <jats:sub>H</jats:sub> 17 induction by <jats:italic>E. gallinarum</jats:italic> . Translocation of the pathobiont triggered increased anti-RNA autoantibody titers that correlated with renal autoimmune pathophysiology in murine gnotobiotic lupus models and with disease activity in patients with SLE. These studies elucidate cellular mechanisms of how a translocating gut pathobiont induces systemic human T cell– and B cell–dependent autoimmune responses and provide a framework for developing host- and microbiota-derived biomarkers and targeted therapies in autoimmune diseases.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"41 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143125402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Brittany Lipchick, Adam N. Guterres, Hsin-Yi Chen, Delaine M. Zundell, Segundo Del Aguila, Patricia I. Reyes-Uribe, Yulissa Tirado, Subhasree Basu, Xiangfan Yin, Andrew V. Kossenkov, Yiling Lu, Gordon B. Mills, Qin Liu, Aaron R. Goldman, Maureen E. Murphy, David W. Speicher, Jessie Villanueva
Although oncogenic NRAS activates mitogen-activated protein kinase (MAPK) signaling, inhibition of the MAPK pathway is not therapeutically efficacious in NRAS-mutant (NRASMUT) tumors. Here, we report that selectively silencing the ribosomal protein S6 kinase 2 (S6K2) while preserving the activity of S6K1 perturbs lipid metabolism, enhances fatty acid unsaturation, and triggers lethal lipid peroxidation in NRASMUT melanoma cells that are resistant to MAPK inhibition. S6K2 depletion induces endoplasmic reticulum stress and peroxisome proliferator–activated receptor α (PPARα) activation, triggering cell death selectively in MAPK inhibitor–resistant melanoma. We found that combining PPARα agonists and polyunsaturated fatty acids phenocopied the effects of S6K2 abrogation, blocking tumor growth in both patient-derived xenografts and immunocompetent murine melanoma models. Collectively, our study establishes S6K2 and its effector subnetwork as promising targets for NRASMUT melanomas that are resistant to global MAPK pathway inhibitors.
{"title":"Selective abrogation of S6K2 identifies lipid homeostasis as a survival vulnerability in MAPK inhibitor–resistant NRAS-mutant melanoma","authors":"Brittany Lipchick, Adam N. Guterres, Hsin-Yi Chen, Delaine M. Zundell, Segundo Del Aguila, Patricia I. Reyes-Uribe, Yulissa Tirado, Subhasree Basu, Xiangfan Yin, Andrew V. Kossenkov, Yiling Lu, Gordon B. Mills, Qin Liu, Aaron R. Goldman, Maureen E. Murphy, David W. Speicher, Jessie Villanueva","doi":"","DOIUrl":"","url":null,"abstract":"<div >Although oncogenic NRAS activates mitogen-activated protein kinase (MAPK) signaling, inhibition of the MAPK pathway is not therapeutically efficacious in <i>NRAS</i>-mutant (<i>NRAS</i><sup>MUT</sup>) tumors. Here, we report that selectively silencing the ribosomal protein S6 kinase 2 (S6K2) while preserving the activity of S6K1 perturbs lipid metabolism, enhances fatty acid unsaturation, and triggers lethal lipid peroxidation in <i>NRAS</i><sup>MUT</sup> melanoma cells that are resistant to MAPK inhibition. S6K2 depletion induces endoplasmic reticulum stress and peroxisome proliferator–activated receptor α (PPARα) activation, triggering cell death selectively in MAPK inhibitor–resistant melanoma. We found that combining PPARα agonists and polyunsaturated fatty acids phenocopied the effects of S6K2 abrogation, blocking tumor growth in both patient-derived xenografts and immunocompetent murine melanoma models. Collectively, our study establishes S6K2 and its effector subnetwork as promising targets for <i>NRAS</i><sup>MUT</sup> melanomas that are resistant to global MAPK pathway inhibitors.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 784","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-05DOI: 10.1126/scitranslmed.adp8913
Brittany Lipchick, Adam N. Guterres, Hsin-Yi Chen, Delaine M. Zundell, Segundo Del Aguila, Patricia I. Reyes-Uribe, Yulissa Tirado, Subhasree Basu, Xiangfan Yin, Andrew V. Kossenkov, Yiling Lu, Gordon B. Mills, Qin Liu, Aaron R. Goldman, Maureen E. Murphy, David W. Speicher, Jessie Villanueva
Although oncogenic NRAS activates mitogen-activated protein kinase (MAPK) signaling, inhibition of the MAPK pathway is not therapeutically efficacious in NRAS -mutant ( NRASMUT ) tumors. Here, we report that selectively silencing the ribosomal protein S6 kinase 2 (S6K2) while preserving the activity of S6K1 perturbs lipid metabolism, enhances fatty acid unsaturation, and triggers lethal lipid peroxidation in NRASMUT melanoma cells that are resistant to MAPK inhibition. S6K2 depletion induces endoplasmic reticulum stress and peroxisome proliferator–activated receptor α (PPARα) activation, triggering cell death selectively in MAPK inhibitor–resistant melanoma. We found that combining PPARα agonists and polyunsaturated fatty acids phenocopied the effects of S6K2 abrogation, blocking tumor growth in both patient-derived xenografts and immunocompetent murine melanoma models. Collectively, our study establishes S6K2 and its effector subnetwork as promising targets for NRASMUT melanomas that are resistant to global MAPK pathway inhibitors.
{"title":"Selective abrogation of S6K2 identifies lipid homeostasis as a survival vulnerability in MAPK inhibitor–resistant NRAS -mutant melanoma","authors":"Brittany Lipchick, Adam N. Guterres, Hsin-Yi Chen, Delaine M. Zundell, Segundo Del Aguila, Patricia I. Reyes-Uribe, Yulissa Tirado, Subhasree Basu, Xiangfan Yin, Andrew V. Kossenkov, Yiling Lu, Gordon B. Mills, Qin Liu, Aaron R. Goldman, Maureen E. Murphy, David W. Speicher, Jessie Villanueva","doi":"10.1126/scitranslmed.adp8913","DOIUrl":"https://doi.org/10.1126/scitranslmed.adp8913","url":null,"abstract":"Although oncogenic NRAS activates mitogen-activated protein kinase (MAPK) signaling, inhibition of the MAPK pathway is not therapeutically efficacious in <jats:italic>NRAS</jats:italic> -mutant ( <jats:italic>NRAS</jats:italic> <jats:sup>MUT</jats:sup> ) tumors. Here, we report that selectively silencing the ribosomal protein S6 kinase 2 (S6K2) while preserving the activity of S6K1 perturbs lipid metabolism, enhances fatty acid unsaturation, and triggers lethal lipid peroxidation in <jats:italic>NRAS</jats:italic> <jats:sup>MUT</jats:sup> melanoma cells that are resistant to MAPK inhibition. S6K2 depletion induces endoplasmic reticulum stress and peroxisome proliferator–activated receptor α (PPARα) activation, triggering cell death selectively in MAPK inhibitor–resistant melanoma. We found that combining PPARα agonists and polyunsaturated fatty acids phenocopied the effects of S6K2 abrogation, blocking tumor growth in both patient-derived xenografts and immunocompetent murine melanoma models. Collectively, our study establishes S6K2 and its effector subnetwork as promising targets for <jats:italic>NRAS</jats:italic> <jats:sup>MUT</jats:sup> melanomas that are resistant to global MAPK pathway inhibitors.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"22 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143125405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-05DOI: 10.1126/scitranslmed.adp1349
Fuyi Liao, Dequan Zhou, Marlene Cano, Zhiyi Liu, Davide Scozzi, Laneshia K. Tague, Derek E. Byers, Wenjun Li, Jothilingam Sivapackiam, Vijay Sharma, Alexander S. Krupnick, Dara W. Frank, Daniel Kreisel, Hrishikesh S. Kulkarni, Ramsey R. Hachem, Andrew E. Gelman
How pathogens inhibit transplant tolerance remains unclear. Here, we found that Pseudomonas aeruginosa infection, but not other common bacterial respiratory infections, increases antibody-mediated rejection (AMR) risk in recipients of lung transplants. To explore this relationship, we performed orthotopic lung transplants in mice, infected recipients with P. aeruginosa , and observed for the development of AMR. Intravital two-photon microscopy showed that P. aeruginosa rapidly invaded bronchial-associated lymphoid tissues, which resulted in acute lymphocytotoxicity, including the death of forkhead box P3 (Foxp3) + CD4 + T cells that are required to suppress AMR. P. aeruginosa –mediated AMR required expression of the type III secretion system (T3SS), which injects exotoxins into the cell cytoplasm. Through a combination of mutagenesis and epitope tagging experiments, we revealed that T3SS exotoxin T ADP ribosyl-transferase activity was sufficient for graft-resident Foxp3 + CD4 + T cell apoptosis, leading to myeloid differentiation primary response 88 (Myd88)–dependent generation of T-box expressed in T cells (T-bet)– and C-X-C motif chemokine receptor 3 (CXCR3)–positive germinal center and memory B cells with high donor antigen avidity. We also found that T-bet + and CXCR3 + B cells were elevated in biopsies from recipients of lung transplants who were diagnosed with AMR. In mice, CXCR3 deficiency restricted to B cells or CXCR3 blockade prevented AMR despite P. aeruginosa infection. Our work has identified a previously unrecognized role of bacterial virulence in lung allograft rejection and suggests potential strategies to prevent AMR for those at high risk of P. aeruginosa infection after transplant.
{"title":"Pseudomonas aeruginosa infection induces intragraft lymphocytotoxicity that triggers lung transplant antibody-mediated rejection","authors":"Fuyi Liao, Dequan Zhou, Marlene Cano, Zhiyi Liu, Davide Scozzi, Laneshia K. Tague, Derek E. Byers, Wenjun Li, Jothilingam Sivapackiam, Vijay Sharma, Alexander S. Krupnick, Dara W. Frank, Daniel Kreisel, Hrishikesh S. Kulkarni, Ramsey R. Hachem, Andrew E. Gelman","doi":"10.1126/scitranslmed.adp1349","DOIUrl":"https://doi.org/10.1126/scitranslmed.adp1349","url":null,"abstract":"How pathogens inhibit transplant tolerance remains unclear. Here, we found that <jats:italic>Pseudomonas aeruginosa</jats:italic> infection, but not other common bacterial respiratory infections, increases antibody-mediated rejection (AMR) risk in recipients of lung transplants. To explore this relationship, we performed orthotopic lung transplants in mice, infected recipients with <jats:italic>P. aeruginosa</jats:italic> , and observed for the development of AMR. Intravital two-photon microscopy showed that <jats:italic>P. aeruginosa</jats:italic> rapidly invaded bronchial-associated lymphoid tissues, which resulted in acute lymphocytotoxicity, including the death of forkhead box P3 (Foxp3) <jats:sup>+</jats:sup> CD4 <jats:sup>+</jats:sup> T cells that are required to suppress AMR. <jats:italic>P. aeruginosa</jats:italic> –mediated AMR required expression of the type III secretion system (T3SS), which injects exotoxins into the cell cytoplasm. Through a combination of mutagenesis and epitope tagging experiments, we revealed that T3SS exotoxin T ADP ribosyl-transferase activity was sufficient for graft-resident Foxp3 <jats:sup>+</jats:sup> CD4 <jats:sup>+</jats:sup> T cell apoptosis, leading to myeloid differentiation primary response 88 (Myd88)–dependent generation of T-box expressed in T cells (T-bet)– and C-X-C motif chemokine receptor 3 (CXCR3)–positive germinal center and memory B cells with high donor antigen avidity. We also found that T-bet <jats:sup>+</jats:sup> and CXCR3 <jats:sup>+</jats:sup> B cells were elevated in biopsies from recipients of lung transplants who were diagnosed with AMR. In mice, CXCR3 deficiency restricted to B cells or CXCR3 blockade prevented AMR despite <jats:italic>P. aeruginosa</jats:italic> infection. Our work has identified a previously unrecognized role of bacterial virulence in lung allograft rejection and suggests potential strategies to prevent AMR for those at high risk of <jats:italic>P. aeruginosa</jats:italic> infection after transplant.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"105 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143125406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fuyi Liao, Dequan Zhou, Marlene Cano, Zhiyi Liu, Davide Scozzi, Laneshia K. Tague, Derek E. Byers, Wenjun Li, Jothilingam Sivapackiam, Vijay Sharma, Alexander S. Krupnick, Dara W. Frank, Daniel Kreisel, Hrishikesh S. Kulkarni, Ramsey R. Hachem, Andrew E. Gelman
How pathogens inhibit transplant tolerance remains unclear. Here, we found that Pseudomonas aeruginosa infection, but not other common bacterial respiratory infections, increases antibody-mediated rejection (AMR) risk in recipients of lung transplants. To explore this relationship, we performed orthotopic lung transplants in mice, infected recipients with P. aeruginosa, and observed for the development of AMR. Intravital two-photon microscopy showed that P. aeruginosa rapidly invaded bronchial-associated lymphoid tissues, which resulted in acute lymphocytotoxicity, including the death of forkhead box P3 (Foxp3)+CD4+ T cells that are required to suppress AMR. P. aeruginosa–mediated AMR required expression of the type III secretion system (T3SS), which injects exotoxins into the cell cytoplasm. Through a combination of mutagenesis and epitope tagging experiments, we revealed that T3SS exotoxin T ADP ribosyl-transferase activity was sufficient for graft-resident Foxp3+CD4+ T cell apoptosis, leading to myeloid differentiation primary response 88 (Myd88)–dependent generation of T-box expressed in T cells (T-bet)– and C-X-C motif chemokine receptor 3 (CXCR3)–positive germinal center and memory B cells with high donor antigen avidity. We also found that T-bet+ and CXCR3+ B cells were elevated in biopsies from recipients of lung transplants who were diagnosed with AMR. In mice, CXCR3 deficiency restricted to B cells or CXCR3 blockade prevented AMR despite P. aeruginosa infection. Our work has identified a previously unrecognized role of bacterial virulence in lung allograft rejection and suggests potential strategies to prevent AMR for those at high risk of P. aeruginosa infection after transplant.
{"title":"Pseudomonas aeruginosa infection induces intragraft lymphocytotoxicity that triggers lung transplant antibody-mediated rejection","authors":"Fuyi Liao, Dequan Zhou, Marlene Cano, Zhiyi Liu, Davide Scozzi, Laneshia K. Tague, Derek E. Byers, Wenjun Li, Jothilingam Sivapackiam, Vijay Sharma, Alexander S. Krupnick, Dara W. Frank, Daniel Kreisel, Hrishikesh S. Kulkarni, Ramsey R. Hachem, Andrew E. Gelman","doi":"","DOIUrl":"","url":null,"abstract":"<div >How pathogens inhibit transplant tolerance remains unclear. Here, we found that <i>Pseudomonas aeruginosa</i> infection, but not other common bacterial respiratory infections, increases antibody-mediated rejection (AMR) risk in recipients of lung transplants. To explore this relationship, we performed orthotopic lung transplants in mice, infected recipients with <i>P. aeruginosa</i>, and observed for the development of AMR. Intravital two-photon microscopy showed that <i>P. aeruginosa</i> rapidly invaded bronchial-associated lymphoid tissues, which resulted in acute lymphocytotoxicity, including the death of forkhead box P3 (Foxp3)<sup>+</sup>CD4<sup>+</sup> T cells that are required to suppress AMR. <i>P. aeruginosa</i>–mediated AMR required expression of the type III secretion system (T3SS), which injects exotoxins into the cell cytoplasm. Through a combination of mutagenesis and epitope tagging experiments, we revealed that T3SS exotoxin T ADP ribosyl-transferase activity was sufficient for graft-resident Foxp3<sup>+</sup>CD4<sup>+</sup> T cell apoptosis, leading to myeloid differentiation primary response 88 (Myd88)–dependent generation of T-box expressed in T cells (T-bet)– and C-X-C motif chemokine receptor 3 (CXCR3)–positive germinal center and memory B cells with high donor antigen avidity. We also found that T-bet<sup>+</sup> and CXCR3<sup>+</sup> B cells were elevated in biopsies from recipients of lung transplants who were diagnosed with AMR. In mice, CXCR3 deficiency restricted to B cells or CXCR3 blockade prevented AMR despite <i>P. aeruginosa</i> infection. Our work has identified a previously unrecognized role of bacterial virulence in lung allograft rejection and suggests potential strategies to prevent AMR for those at high risk of <i>P. aeruginosa</i> infection after transplant.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 784","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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