OncogenePub Date : 2024-11-07DOI: 10.1038/s41388-024-03206-x
Carolin Offenhäuser, Keyur A Dave, Kirrilee J Beckett, Fiona M Smith, Buddhika A Jayakody, Leanne T Cooper, Helen Agyei-Yeboah, Jennifer K McCarron, Yuchen Li, Kate Bastick, Fares Al-Ejeh, Jason K Cullen, Mark G Coulthard, Jeffrey J Gorman, Andrew W Boyd, Bryan W Day
{"title":"EphA2 regulates vascular permeability and prostate cancer metastasis via modulation of cell junction protein phosphorylation.","authors":"Carolin Offenhäuser, Keyur A Dave, Kirrilee J Beckett, Fiona M Smith, Buddhika A Jayakody, Leanne T Cooper, Helen Agyei-Yeboah, Jennifer K McCarron, Yuchen Li, Kate Bastick, Fares Al-Ejeh, Jason K Cullen, Mark G Coulthard, Jeffrey J Gorman, Andrew W Boyd, Bryan W Day","doi":"10.1038/s41388-024-03206-x","DOIUrl":"https://doi.org/10.1038/s41388-024-03206-x","url":null,"abstract":"<p><p>Prostate cancer morbidity and mortality demonstrate a need for more effective targeted therapies. One potential target is EphA2, although paradoxically, pro- and anti-oncogenic effects have been shown to be mediated by EphA2. We demonstrate that unique activating and blocking EphA2-targeting monoclonal antibodies display opposing tumor-suppressive and oncogenic properties in vivo. To further explore this complexity, we performed detailed phosphoproteomic analysis following ligand-induced EphA2 activation. Our analysis identified altered phosphorylation of 73 downstream proteins related to the PI3K/AKT/mTOR and ERK/MAPK pathways, with the majority implicated in cell junction and cytoskeletal organization, cell motility, and tumor metastasis. We demonstrate that the adapter protein SHB is an essential component in mediating the inhibition of the ERK/MAPK pathway in response to EphA2 receptor activation. Furthermore, we identify the adherence junction protein afadin as an EphA2-regulated phosphoprotein which is involved in prostate cancer migration and invasion.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142605747","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}
OncogenePub Date : 2024-11-07DOI: 10.1038/s41388-024-03190-2
Shekha Tahsin, Neha S Sane, Brent Cernyar, Linan Jiang, Yitshak Zohar, Benjamin R Lee, Cindy K Miranti
{"title":"Correction: AR loss in prostate cancer stroma mediated by NF-κB and p38-MAPK signaling disrupts stromal morphogen production.","authors":"Shekha Tahsin, Neha S Sane, Brent Cernyar, Linan Jiang, Yitshak Zohar, Benjamin R Lee, Cindy K Miranti","doi":"10.1038/s41388-024-03190-2","DOIUrl":"https://doi.org/10.1038/s41388-024-03190-2","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142605741","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}
OncogenePub Date : 2024-11-07DOI: 10.1038/s41388-024-03210-1
Cheryl Cero, John S House, Vincenzo Verdi, Jordan L Ferguson, Dereje D Jima, Aubrie A Selmek, Olivia M Patania, Jennifer E Dwyer, Bih-Rong Wei, Dillon T Lloyd, Heather R Shive
{"title":"Profiling the cancer-prone microenvironment in a zebrafish model for MPNST.","authors":"Cheryl Cero, John S House, Vincenzo Verdi, Jordan L Ferguson, Dereje D Jima, Aubrie A Selmek, Olivia M Patania, Jennifer E Dwyer, Bih-Rong Wei, Dillon T Lloyd, Heather R Shive","doi":"10.1038/s41388-024-03210-1","DOIUrl":"https://doi.org/10.1038/s41388-024-03210-1","url":null,"abstract":"<p><p>Microenvironmental contributions to soft tissue sarcoma progression are relatively undefined, particularly during sarcoma onset. Use of animal models to reveal these contributions is impeded by difficulties in discriminating between microenvironmental, precancerous, and cancer cells, and challenges in defining a precancerous microenvironment. We developed a zebrafish model that allows segregation of microenvironmental, precancerous, and cancerous cell populations by fluorescence-activated cell sorting. This model has high predilection for malignant peripheral nerve sheath tumor (MPNST), a type of soft tissue sarcoma that exhibits rapid, aggressive growth. Using RNA-seq, we profiled the transcriptomes of microenvironmental, precancerous, and cancer cells from our zebrafish MPNST model. We show broad activation of inflammation/immune-associated signaling networks, describe gene expression patterns that uniquely characterize the transition from precancerous to cancer ME, and identify macrophages as potential contributors to microenvironmental phenotypes. We identify conserved gene expression changes and candidate genes of interest by comparative genomics analysis of MPNST versus benign lesions in both humans and zebrafish. Finally, we functionally validate a candidate extracellular matrix protein, periostin (POSTN), in human MPNST. This work provides insight into how the microenvironment may regulate MPNST initiation and progression.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142605754","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}
{"title":"Hypoxia induced cellular and exosomal RPPH1 promotes breast cancer angiogenesis and metastasis through stabilizing the IGF2BP2/FGFR2 axis.","authors":"Wentao Ning, Jingyan Yang, Ruiqi Ni, Qianqian Yin, Manqi Zhang, Fangfang Zhang, Yue Yang, Yanfeng Zhang, Meng Cao, Liang Jin, Yi Pan","doi":"10.1038/s41388-024-03213-y","DOIUrl":"10.1038/s41388-024-03213-y","url":null,"abstract":"<p><p>Metastasis is the major cause of breast cancer mortality, with angiogenesis and tumor-released exosomes playing key roles. However, the communication between breast cancer cells and endothelial cells and its role in tumor metastasis remains unclear. Here, we characterize a long noncoding RNA, RPPH1, which is upregulated in breast cancer tissues and positively associated with poor prognosis. Hypoxia microenvironment upregulates the expression of RPPH1 in breast cancer cells, and promotes its packaging into exosomes through hnRNPA1, leading to the maintenance of stemness and aggressive traits in cancer cells and angiogenesis in endothelial cells. The function of cellular and exosomal RPPH1 was confirmed in the MMTV-PyMT mouse model, in which ASO-RPPH1 therapy effectively inhibited tumor progression and metastasis. Mechanistically, RPPH1 protects IGF2BP2 from ubiquitination-induced degradation, stabilizes N6-methyladenosine (m6A)-modified FGFR2 mRNA, and activates the PI3K/AKT pathway. Our research unveils the role of RPPH1 in breast cancer metastasis and highlights its potential as a therapeutic target.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576726","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}
OncogenePub Date : 2024-11-03DOI: 10.1038/s41388-024-03208-9
Khalid N M Abdelazeem, Diemmy Nguyen, Sophia Corbo, Laurel B Darragh, Mike W Matsumoto, Benjamin Van Court, Brooke Neupert, Justin Yu, Nicholas A Olimpo, Douglas Grant Osborne, Jacob Gadwa, Richard B Ross, Alexander Nguyen, Shilpa Bhatia, Mohit Kapoor, Rachel S Friedman, Jordan Jacobelli, Anthony J Saviola, Michael W Knitz, Elena B Pasquale, Sana D Karam
{"title":"Manipulating the EphB4-ephrinB2 axis to reduce metastasis in HNSCC.","authors":"Khalid N M Abdelazeem, Diemmy Nguyen, Sophia Corbo, Laurel B Darragh, Mike W Matsumoto, Benjamin Van Court, Brooke Neupert, Justin Yu, Nicholas A Olimpo, Douglas Grant Osborne, Jacob Gadwa, Richard B Ross, Alexander Nguyen, Shilpa Bhatia, Mohit Kapoor, Rachel S Friedman, Jordan Jacobelli, Anthony J Saviola, Michael W Knitz, Elena B Pasquale, Sana D Karam","doi":"10.1038/s41388-024-03208-9","DOIUrl":"10.1038/s41388-024-03208-9","url":null,"abstract":"<p><p>The EphB4-ephrinB2 signaling axis has been heavily implicated in metastasis across numerous cancer types. Our emerging understanding of the dichotomous roles that EphB4 and ephrinB2 play in head and neck squamous cell carcinoma (HNSCC) poses a significant challenge to rational drug design. We find that EphB4 knockdown in cancer cells enhances metastasis in preclinical HNSCC models by augmenting immunosuppressive cells like T regulatory cells (Tregs) within the tumor microenvironment. EphB4 inhibition in cancer cells also amplifies their ability to metastasize through increased expression of genes associated with hallmark pathways of metastasis along with classical and non-classical epithelial-mesenchymal transition. In contrast, vascular ephrinB2 knockout coupled with radiation therapy (RT) enhances anti-tumor immunity, reduces Treg accumulation into the tumor, and decreases metastasis. Notably, targeting the EphB4-ephrinB2 signaling axis with the engineered ligands ephrinB2-Fc-His and Fc-TNYL-RAW-GS reduces local tumor growth and distant metastasis in a preclinical model of HNSCC. Our data suggests that targeted inhibition of vascular ephrinB2 while avoiding inhibition of EphB4 in cancer cells could be a promising strategy to mitigate HNSCC metastasis.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567728","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}
{"title":"The Ku70-SIX1-GPT2 axis regulates alpha-ketoglutarate metabolism to drive progression of prostate cancer.","authors":"Hongbiao Huang, Xuefen Zhuang, Shusha Yin, Wenshuang Sun, Ji Cheng, E-Ying Peng, Yujie Xiang, Xiaoyue He, Mengfan Tang, Yuting Li, Yu Yao, Yuanfei Deng, Qing Liu, Zhenlong Shao, Xiaohong Xia, Gengxi Cai, Yuning Liao","doi":"10.1038/s41388-024-03209-8","DOIUrl":"10.1038/s41388-024-03209-8","url":null,"abstract":"<p><p>Sine oculis homeobox homolog 1 (SIX1) is a new identified cancer driver in the development of prostate cancer (PC). However, the upstream regulatory mechanisms for SIX1 reactivation in cancer remains elusive. Here, we found that Ku70 robustly interacts with SIX1 in the nucleus of PC cells. The HD domain of SIX1 and the DBD domain of Ku70 are required for formation of Ku70-SIX1 complex. 20 groups of hydrogen bonds were identified in this complex by molecular dynamics simulation. Depletion of Ku70/SIX1 notably abrogates the proliferation and migration of PC. Further studies revealed that SIX1 is recruited to the promoter region on glutamate-pyruvate transaminase 2 (GPT2). Ku70 enhances the SIX1-mediated transcriptional activation on GPT2, thereby facilitating the generation of alpha-ketoglutarate (α-KG). In addition, formation of the Ku70-SIX1 complex promotes GPT2-dependent cell proliferation and migration in PC. Moreover, the expression of GPT2 is upregulated and strongly correlated with the expression of Ku70/SIX1 in PC tissues. In summary, our findings not only provide insight into the mechanistic interactions between Ku70 and SIX1, but also highlight the significance of the Ku70-SIX1-GPT2 axis for α-KG metabolism and PC carcinogenesis.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564881","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}
OncogenePub Date : 2024-11-01DOI: 10.1038/s41388-024-03197-9
Chunxiao Zhang, Taisen Hao, Alessia Bortoluzzi, Min-Hsuan Chen, Xiwei Wu, Jinhui Wang, Richard Ermel, Young Kim, Shiuan Chen, WenYong Chen
{"title":"Sex-dependent differences in hematopoietic stem cell aging and leukemogenic potential.","authors":"Chunxiao Zhang, Taisen Hao, Alessia Bortoluzzi, Min-Hsuan Chen, Xiwei Wu, Jinhui Wang, Richard Ermel, Young Kim, Shiuan Chen, WenYong Chen","doi":"10.1038/s41388-024-03197-9","DOIUrl":"10.1038/s41388-024-03197-9","url":null,"abstract":"<p><p>Sex influences many biological outcomes, but how sex affects hematopoietic stem cell (HSC) aging and hematological disorders is poorly understood. The widespread use of young animal models to study age-related diseases further complicates these matters. Using aged and long-lived BALB/c mouse models, we discovered that aging mice exhibit sex-dependent disparities, mirroring aging humans, in developing myeloid skewing, anemia, and leukemia. These disparities are underlined by sex-differentiated HSC aging characteristics across the population, single-cell, and molecular levels. The HSC population expanded significantly with aging and longevity in males, but this occurred to a much lesser degree in aging females that instead expanded committed progenitors. Aging male HSCs are more susceptible to BCR-ABL1 transformation with faster development of chronic myeloid leukemia (CML) than female HSCs. Additionally, the loss of the aging regulator Sirt1 inhibited CML development in aging male but not female mice. Our results showed for the first time that sex-differentiated HSC aging impacts hematopoiesis, leukemogenesis, and certain gene functions. This discovery provides insights into understanding age-dependent hematological diseases and sex-targeted strategies for the treatment and prevention of certain blood disorders and cancer.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564879","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}
OncogenePub Date : 2024-11-01DOI: 10.1038/s41388-024-03199-7
Maryne Dupuy, Maxime Gueguinou, Anaïs Postec, Régis Brion, Robel Tesfaye, Mathilde Mullard, Laura Regnier, Jérôme Amiaud, Clémence Hubsch, Marie Potier-Cartereau, Aurélie Chantôme, Bénédicte Brounais-Le Royer, Marc Baud'huin, Steven Georges, François Lamoureux, Benjamin Ory, Natacha Entz-Werlé, Olivier Delattre, Françoise Rédini, Christophe Vandier, Franck Verrecchia
{"title":"Chimeric protein EWS::FLI1 drives cell proliferation in Ewing Sarcoma via aberrant expression of KCNN1/SK1 and dysregulation of calcium signaling.","authors":"Maryne Dupuy, Maxime Gueguinou, Anaïs Postec, Régis Brion, Robel Tesfaye, Mathilde Mullard, Laura Regnier, Jérôme Amiaud, Clémence Hubsch, Marie Potier-Cartereau, Aurélie Chantôme, Bénédicte Brounais-Le Royer, Marc Baud'huin, Steven Georges, François Lamoureux, Benjamin Ory, Natacha Entz-Werlé, Olivier Delattre, Françoise Rédini, Christophe Vandier, Franck Verrecchia","doi":"10.1038/s41388-024-03199-7","DOIUrl":"https://doi.org/10.1038/s41388-024-03199-7","url":null,"abstract":"<p><p>Ewing sarcoma (ES) is characterized by EWS::FLI1 or EWS::ERG fusion proteins. Knowing that ion channels are involved in tumorigenesis, this work aimed to study the involvement of the KCNN1 gene, which encodes the SK1 potassium channel, in ES development. Bioinformatics analyses from databases were used to study KCNN1 expression in patients and cell lines. Molecular approaches and in vitro assays were used to study the transcriptional regulation of KCNN1 and its involvement in the regulation of ES cell proliferation. KCNN1 is overexpressed in ES patient biopsies, and its expression is inversely correlated with patient survival. EWS::FLI1, like EWS::ERG, promotes KCNN1 and SK1 expression, binding to GGAA microsatellites near the promoter of KCNN1 isoforms. KCNN1 is involved in the regulation of ES cell proliferation, with its silencing being associated with a slowing of the cell cycle, and its expression modulates membrane potential and therefore calcium flux. These results highlight that KCNN1 is a direct target of EWS::FLI1 and EWS::ERG and demonstrate that KCNN1 is involved in the regulation of intracellular calcium activity and ES cell proliferation, making it a promising therapeutic target in ES.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564877","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}
OncogenePub Date : 2024-10-29DOI: 10.1038/s41388-024-03200-3
Teresa Börding, Tobias Janik, Philip Bischoff, Markus Morkel, Christine Sers, David Horst
{"title":"GPA33 expression in colorectal cancer can be induced by WNT inhibition and targeted by cellular therapy.","authors":"Teresa Börding, Tobias Janik, Philip Bischoff, Markus Morkel, Christine Sers, David Horst","doi":"10.1038/s41388-024-03200-3","DOIUrl":"https://doi.org/10.1038/s41388-024-03200-3","url":null,"abstract":"<p><p>GPA33 is a promising surface antigen for targeted therapy in colorectal cancer (CRC). It is expressed almost exclusively in CRC and intestinal epithelia. However, previous clinical studies have not achieved expected response rates. We investigated GPA33 expression and regulation in CRC and developed a GPA33-targeted cellular therapy. We examined GPA33 expression in CRC cohorts using immunohistochemistry and immunofluorescence. We analyzed GPA33 regulation by interference with oncogenic signaling in vitro and in vivo using inhibitors and conditional inducible regulators. Furthermore, we engineered anti-GPA33-CAR T cells and assessed their activity in vitro and in vivo. GPA33 expression showed consistent intratumoral heterogeneity in CRC with antigen loss at the infiltrative tumor edge. This pattern was preserved at metastatic sites. GPA33-positive cells had a differentiated phenotype and low WNT activity. Low GPA33 expression levels were linked to tumor progression in patients with CRC. Downregulation of WNT activity induced GPA33 expression in vitro and in GPA33-negative tumor cell subpopulations in xenografts. GPA33-CAR T cells were activated in response to GPA33 and reduced xenograft growth in mice after intratumoral application. GPA33-targeted therapy may be improved by simultaneous WNT inhibition to enhance GPA33 expression. Furthermore, GPA33 is a promising target for cellular immunotherapy in CRC.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546623","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}
OncogenePub Date : 2024-10-29DOI: 10.1038/s41388-024-03191-1
Joanne D Tejero, Rebecca S Hesterberg, Stanislav Drapela, Didem Ilter, Devesh Raizada, Felicia Lazure, Hossein Kashfi, Min Liu, Leonardo Silvane, Dorina Avram, Juan Fernández-García, John M Asara, Sarah-Maria Fendt, John L Cleveland, Ana P Gomes
{"title":"Methylmalonic acid induces metabolic abnormalities and exhaustion in CD8<sup>+</sup> T cells to suppress anti-tumor immunity.","authors":"Joanne D Tejero, Rebecca S Hesterberg, Stanislav Drapela, Didem Ilter, Devesh Raizada, Felicia Lazure, Hossein Kashfi, Min Liu, Leonardo Silvane, Dorina Avram, Juan Fernández-García, John M Asara, Sarah-Maria Fendt, John L Cleveland, Ana P Gomes","doi":"10.1038/s41388-024-03191-1","DOIUrl":"https://doi.org/10.1038/s41388-024-03191-1","url":null,"abstract":"<p><p>Systemic levels of methylmalonic acid (MMA), a byproduct of propionate metabolism, increase with age and MMA promotes tumor progression via its direct effects in tumor cells. However, the role of MMA in modulating the tumor ecosystem remains to be investigated. The proliferation and function of CD8<sup>+</sup> T cells, key anti-tumor immune cells, declines with age and in conditions of vitamin B12 deficiency, which are the two most well-established conditions that lead to increased systemic levels of MMA. Thus, we hypothesized that increased circulatory levels of MMA would lead to a suppression of CD8<sup>+</sup> T cell immunity. Treatment of primary CD8<sup>+</sup> T cells with MMA induced a dysfunctional phenotype characterized by robust immunosuppressive transcriptional reprogramming and marked increases in the expression of the exhaustion regulator, TOX. Accordingly, MMA treatment upregulated exhaustion markers in CD8<sup>+</sup> T cells and decreased their effector functions, which drove the suppression of anti-tumor immunity in vitro and in vivo. Mechanistically, MMA-induced CD8<sup>+</sup> T cell exhaustion was associated with a suppression of NADH-regenerating reactions in the TCA cycle and concomitant defects in mitochondrial function. Thus, MMA has immunomodulatory roles, thereby highlighting MMA as an important link between aging, immune dysfunction, and cancer.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546624","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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