Pub Date : 2025-04-03DOI: 10.1016/j.ccell.2025.03.013
Suhaib K. Abdeen, Ignacio Mastandrea, Nina Stinchcombe, Jens Puschhof, Eran Elinav
Diet impacts cancer in diverse manners. Multiple nutritional effects on tumors are mediated by dietary modulation of commensals, residing in mucosal surfaces and possibly also within the tumor microenvironment. Mechanistically understanding such diet-microbiome-host interactions may enable to develop precision nutritional interventions impacting cancer development, dissemination, and treatment responses. However, data-driven nutritional strategies integrating diet-microbiome interactions are infrequently incorporated into cancer prevention and treatment schemes. Herein, we discuss how dietary composition affects cancer-related processes through alterations exerted by specific nutrients and complex foods on the microbiome. We highlight how dietary timing, including time-restricted feeding, impacts microbial function in modulating cancer and its therapy. We review existing and experimental nutritional approaches aimed at enhancing microbiome-mediated cancer treatment responsiveness while minimizing adverse effects, and address challenges and prospects in integrating diet-microbiome interactions into precision oncology. Collectively, mechanistically understanding diet-microbiome-host interactomes may enable to achieve a personalized and microbiome-informed optimization of nutritional cancer interventions.
{"title":"Diet-microbiome interactions in cancer","authors":"Suhaib K. Abdeen, Ignacio Mastandrea, Nina Stinchcombe, Jens Puschhof, Eran Elinav","doi":"10.1016/j.ccell.2025.03.013","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.03.013","url":null,"abstract":"Diet impacts cancer in diverse manners. Multiple nutritional effects on tumors are mediated by dietary modulation of commensals, residing in mucosal surfaces and possibly also within the tumor microenvironment. Mechanistically understanding such diet-microbiome-host interactions may enable to develop precision nutritional interventions impacting cancer development, dissemination, and treatment responses. However, data-driven nutritional strategies integrating diet-microbiome interactions are infrequently incorporated into cancer prevention and treatment schemes. Herein, we discuss how dietary composition affects cancer-related processes through alterations exerted by specific nutrients and complex foods on the microbiome. We highlight how dietary timing, including time-restricted feeding, impacts microbial function in modulating cancer and its therapy. We review existing and experimental nutritional approaches aimed at enhancing microbiome-mediated cancer treatment responsiveness while minimizing adverse effects, and address challenges and prospects in integrating diet-microbiome interactions into precision oncology. Collectively, mechanistically understanding diet-microbiome-host interactomes may enable to achieve a personalized and microbiome-informed optimization of nutritional cancer interventions.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"16 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766916","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}
Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates found in numerous cancers, often linked to enhanced immunotherapy responses and better clinical outcomes. However, the factors driving TLS maturation are not fully understood. Using near single-cell spatial transcriptomic mapping, we comprehensively profile TLSs under various maturation stages and their microenvironment in hepatocellular carcinoma (HCC). Based on their developmental trajectories, we classify immature TLSs into two groups: conforming and deviating TLSs. Our findings indicate that conforming TLSs, similar to mature TLSs, possess a niche function for immunotherapy responses, while deviating TLSs do not. We discover that the tryptophan-enriched metabolic microenvironment shaped by malignant cells contributes to the deviation of TLS maturation. Inhibiting tryptophan metabolism promotes intratumoral TLS maturation and enhances tumor control, synergizing with anti-PD-1 treatments. Therefore, promoting TLS maturation represents a potential strategy to improve antitumor responses and immunotherapy outcomes.
{"title":"Spatial transcriptomics reveals tryptophan metabolism restricting maturation of intratumoral tertiary lymphoid structures","authors":"Zhonghui Tang, Yinqi Bai, Qi Fang, Yuchen Yuan, Qianwen Zeng, Shuling Chen, Tianyi Xu, Jianyu Chen, Li Tan, Chunqing Wang, Qian Li, Jinpei Lin, Zhuoxuan Yang, Xia Wu, Guowei Shi, Ji Wang, Changjun Yin, Jianping Guo, Shiping Liu, Sui Peng, Ming Kuang","doi":"10.1016/j.ccell.2025.03.011","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.03.011","url":null,"abstract":"Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates found in numerous cancers, often linked to enhanced immunotherapy responses and better clinical outcomes. However, the factors driving TLS maturation are not fully understood. Using near single-cell spatial transcriptomic mapping, we comprehensively profile TLSs under various maturation stages and their microenvironment in hepatocellular carcinoma (HCC). Based on their developmental trajectories, we classify immature TLSs into two groups: conforming and deviating TLSs. Our findings indicate that conforming TLSs, similar to mature TLSs, possess a niche function for immunotherapy responses, while deviating TLSs do not. We discover that the tryptophan-enriched metabolic microenvironment shaped by malignant cells contributes to the deviation of TLS maturation. Inhibiting tryptophan metabolism promotes intratumoral TLS maturation and enhances tumor control, synergizing with anti-PD-1 treatments. Therefore, promoting TLS maturation represents a potential strategy to improve antitumor responses and immunotherapy outcomes.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"10 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766921","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 : 2025-04-03DOI: 10.1016/j.ccell.2025.03.016
Shunrong Ji, Lihua Cao, Jing Gao, Yang Du, Zeng Ye, Xin Lou, Fen Liu, Yehan Zhang, Junfeng Xu, Xiaohan Shi, Huan Wang, Penghao Li, Yikai Li, Hongxu Chen, Zhicheng Yang, Suizhi Gao, Wuhu Zhang, Dan Huang, Shujuan Ni, Miaoyan Wei, Xianjun Yu
The majority of neuroendocrine neoplasms in pancreas are non-functional pancreatic neuroendocrine tumors (NF-PanNETs), which exhibit a high occurrence of distant metastases with limited therapeutic options. Here, we perform a comprehensive molecular characterization of 108 NF-PanNETs through integrative analysis of genomic, transcriptomic, proteomic, and phosphoproteomic profiles. Proteogenomic analysis provides functional insights into the genomic driver alterations of NF-PanNETs, revealing a potential mediator of MEN1 alterations using Men1-conditional knockout mice. Machine-learning-based modeling uncovers a three-protein signature as an independent prognostic factor, which is validated by an independent external cohort. Proteomic and phosphoproteomic-based stratification identifies four subtypes with distinct molecular characteristics, immune microenvironments, and clinicopathological features. Drug screening using patient-derived tumor organoids identifies cyclin-dependent kinase (CDK) 5 and Calcium Voltage-Gated Channel Subunit Alpha1 D (CACNA1D) as ubiquitous and subtype-specific targets, respectively, with in vivo validation using xenograft models. Together, our proteogenomic analyses illustrate a comprehensive molecular landscape of NF-PanNETs, revealing biological insights and therapeutic vulnerabilities.
{"title":"Proteogenomic characterization of non-functional pancreatic neuroendocrine tumors unravels clinically relevant subgroups","authors":"Shunrong Ji, Lihua Cao, Jing Gao, Yang Du, Zeng Ye, Xin Lou, Fen Liu, Yehan Zhang, Junfeng Xu, Xiaohan Shi, Huan Wang, Penghao Li, Yikai Li, Hongxu Chen, Zhicheng Yang, Suizhi Gao, Wuhu Zhang, Dan Huang, Shujuan Ni, Miaoyan Wei, Xianjun Yu","doi":"10.1016/j.ccell.2025.03.016","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.03.016","url":null,"abstract":"The majority of neuroendocrine neoplasms in pancreas are non-functional pancreatic neuroendocrine tumors (NF-PanNETs), which exhibit a high occurrence of distant metastases with limited therapeutic options. Here, we perform a comprehensive molecular characterization of 108 NF-PanNETs through integrative analysis of genomic, transcriptomic, proteomic, and phosphoproteomic profiles. Proteogenomic analysis provides functional insights into the genomic driver alterations of NF-PanNETs, revealing a potential mediator of <em>MEN1</em> alterations using <em>Men1</em>-conditional knockout mice. Machine-learning-based modeling uncovers a three-protein signature as an independent prognostic factor, which is validated by an independent external cohort. Proteomic and phosphoproteomic-based stratification identifies four subtypes with distinct molecular characteristics, immune microenvironments, and clinicopathological features. Drug screening using patient-derived tumor organoids identifies cyclin-dependent kinase (CDK) 5 and Calcium Voltage-Gated Channel Subunit Alpha1 D (CACNA1D) as ubiquitous and subtype-specific targets, respectively, with <em>in vivo</em> validation using xenograft models. Together, our proteogenomic analyses illustrate a comprehensive molecular landscape of NF-PanNETs, revealing biological insights and therapeutic vulnerabilities.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"133 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766926","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 : 2025-04-03DOI: 10.1016/j.ccell.2025.03.014
The Marathon of Hope Cancer Centres Network (MOHCCN), led by the Terry Fox Research Institute and the Terry Fox Foundation, unites researchers, clinicians, patients, funders, and other partners across Canada to accelerate precision oncology, promote collaboration and data sharing, and ultimately improve patient outcomes. This overview outlines the Network’s goals, history, and challenges and opportunities. We also highlight progress toward the “MOHCCN Gold Cohort,” a shared resource of clinical and genomic data from 15,000 patients.
{"title":"The Terry Fox Research Institute Marathon of Hope Cancer Centres Network: A pan-Canadian precision oncology initiative","authors":"","doi":"10.1016/j.ccell.2025.03.014","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.03.014","url":null,"abstract":"The Marathon of Hope Cancer Centres Network (<span><span>MOHCCN</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>), led by the Terry Fox Research Institute and the Terry Fox Foundation, unites researchers, clinicians, patients, funders, and other partners across Canada to accelerate precision oncology, promote collaboration and data sharing, and ultimately improve patient outcomes. This overview outlines the Network’s goals, history, and challenges and opportunities. We also highlight progress toward the “MOHCCN Gold Cohort,” a shared resource of clinical and genomic data from 15,000 patients.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"37 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766839","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 : 2025-04-03DOI: 10.1016/j.ccell.2025.03.015
Yinghua Zhu, Ziwei Zhou, Xin Du, Xiaorong Lin, Zhi-Mei Liang, Si Chen, Yiwei Sun, Yue Wang, Zhenkun Na, Zhiyong Wu, Jiaxin Zhong, Beinan Han, Xiangping Zhu, Wenkui Fu, Hongde Li, Man-Li Luo, Hai Hu
Arginine metabolism reshapes the tumor microenvironment (TME) into a pro-tumor niche through complex metabolic cross-feeding among various cell types. However, the key intercellular metabolic communication that mediates the collective effects of arginine metabolism within the TME remains unclear. Here, we reveal that the metabolic interplay between cancer cells and macrophages plays a dominant role in arginine-driven breast cancer progression. Within the TME, breast cancer cells serve as the primary source of arginine, which induces a pro-tumor polarization of tumor-associated macrophages (TAMs), thereby suppressing the anti-tumor activity of CD8+ T cells. Notably, this cancer cell-macrophage interaction overrides the arginine-mediated enhancement of CD8+ T cell anti-tumor activity. Mechanistically, polyamines derived from arginine metabolism enhance pro-tumor TAM polarization via thymine DNA glycosylase (TDG)-mediated DNA demethylation, regulated by p53 signaling. Importantly, targeting the arginine-polyamine-TDG axis between cancer cells and macrophages significantly suppresses breast cancer growth, highlighting its therapeutic potential.
{"title":"Cancer cell-derived arginine fuels polyamine biosynthesis in tumor-associated macrophages to promote immune evasion","authors":"Yinghua Zhu, Ziwei Zhou, Xin Du, Xiaorong Lin, Zhi-Mei Liang, Si Chen, Yiwei Sun, Yue Wang, Zhenkun Na, Zhiyong Wu, Jiaxin Zhong, Beinan Han, Xiangping Zhu, Wenkui Fu, Hongde Li, Man-Li Luo, Hai Hu","doi":"10.1016/j.ccell.2025.03.015","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.03.015","url":null,"abstract":"Arginine metabolism reshapes the tumor microenvironment (TME) into a pro-tumor niche through complex metabolic cross-feeding among various cell types. However, the key intercellular metabolic communication that mediates the collective effects of arginine metabolism within the TME remains unclear. Here, we reveal that the metabolic interplay between cancer cells and macrophages plays a dominant role in arginine-driven breast cancer progression. Within the TME, breast cancer cells serve as the primary source of arginine, which induces a pro-tumor polarization of tumor-associated macrophages (TAMs), thereby suppressing the anti-tumor activity of CD8<sup>+</sup> T cells. Notably, this cancer cell-macrophage interaction overrides the arginine-mediated enhancement of CD8<sup>+</sup> T cell anti-tumor activity. Mechanistically, polyamines derived from arginine metabolism enhance pro-tumor TAM polarization via thymine DNA glycosylase (TDG)-mediated DNA demethylation, regulated by p53 signaling. Importantly, targeting the arginine-polyamine-TDG axis between cancer cells and macrophages significantly suppresses breast cancer growth, highlighting its therapeutic potential.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"216 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766922","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 : 2025-03-27DOI: 10.1016/j.ccell.2025.03.009
Timothy P. Heffernan, Giulio F. Draetta
In recent decades, we’ve witnessed tremendous advances in oncology with an increase in drug approvals across various modalities and indications, enabled by breakthroughs in personalized medicine, fundamental discoveries in cancer biology, advances in biotechnology, and the growing power of data science. Cancer, however, remains the leading cause of death worldwide, highlighting the need for a transformative approach to clinical care. We propose a shift in industry-academia partnerships that realigns cultural and financial priorities, leveraging advances in pharmaceutical R&D alongside academic innovation throughout the research continuum.
{"title":"Advocating for change—Integration of efforts across the drug discovery and development continuum","authors":"Timothy P. Heffernan, Giulio F. Draetta","doi":"10.1016/j.ccell.2025.03.009","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.03.009","url":null,"abstract":"In recent decades, we’ve witnessed tremendous advances in oncology with an increase in drug approvals across various modalities and indications, enabled by breakthroughs in personalized medicine, fundamental discoveries in cancer biology, advances in biotechnology, and the growing power of data science. Cancer, however, remains the leading cause of death worldwide, highlighting the need for a transformative approach to clinical care. We propose a shift in industry-academia partnerships that realigns cultural and financial priorities, leveraging advances in pharmaceutical R&D alongside academic innovation throughout the research continuum.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"11 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713601","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 : 2025-03-27DOI: 10.1016/j.ccell.2025.03.003
Chen Weller, Osnat Bartok, Christopher S. McGinnis, Heyilimu Palashati, Tian-Gen Chang, Dmitry Malko, Merav D. Shmueli, Asuteka Nagao, Deborah Hayoun, Ayaka Murayama, Yuriko Sakaguchi, Panagiotis Poulis, Aseel Khatib, Bracha Erlanger Avigdor, Sagi Gordon, Sapir Cohen Shvefel, Marie J. Zemanek, Morten M. Nielsen, Sigalit Boura-Halfon, Shira Sagie, Yardena Samuels
Aberrant peptides presented by major histocompatibility complex (MHC) molecules are targets for tumor eradication, as these peptides can be recognized as foreign by T cells. Protein synthesis in malignant cells is dysregulated, which may result in the generation and presentation of aberrant peptides that can be exploited for T cell-based therapies. To investigate the role of translational dysregulation in immunological tumor control, we disrupt translation fidelity by deleting tRNA wybutosine (yW)-synthesizing protein 2 (TYW2) in tumor cells and characterize the downstream impact on translation fidelity and immunogenicity using immunopeptidomics, genomics, and functional assays. These analyses reveal that TYW2 knockout (KO) cells generate immunogenic out-of-frame peptides. Furthermore, Tyw2 loss increases tumor immunogenicity and leads to anti-programmed cell death 1 (PD-1) checkpoint blockade sensitivity in vivo. Importantly, reduced TYW2 expression is associated with increased response to checkpoint blockade in patients. Together, we demonstrate that defects in translation fidelity drive tumor immunogenicity and may be leveraged for cancer immunotherapy.
{"title":"Translation dysregulation in cancer as a source for targetable antigens","authors":"Chen Weller, Osnat Bartok, Christopher S. McGinnis, Heyilimu Palashati, Tian-Gen Chang, Dmitry Malko, Merav D. Shmueli, Asuteka Nagao, Deborah Hayoun, Ayaka Murayama, Yuriko Sakaguchi, Panagiotis Poulis, Aseel Khatib, Bracha Erlanger Avigdor, Sagi Gordon, Sapir Cohen Shvefel, Marie J. Zemanek, Morten M. Nielsen, Sigalit Boura-Halfon, Shira Sagie, Yardena Samuels","doi":"10.1016/j.ccell.2025.03.003","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.03.003","url":null,"abstract":"Aberrant peptides presented by major histocompatibility complex (MHC) molecules are targets for tumor eradication, as these peptides can be recognized as foreign by T cells. Protein synthesis in malignant cells is dysregulated, which may result in the generation and presentation of aberrant peptides that can be exploited for T cell-based therapies. To investigate the role of translational dysregulation in immunological tumor control, we disrupt translation fidelity by deleting tRNA wybutosine (yW)-synthesizing protein 2 (<em>TYW2</em>) in tumor cells and characterize the downstream impact on translation fidelity and immunogenicity using immunopeptidomics, genomics, and functional assays. These analyses reveal that <em>TYW2</em> knockout (KO) cells generate immunogenic out-of-frame peptides. Furthermore, <em>Tyw2</em> loss increases tumor immunogenicity and leads to anti-programmed cell death 1 (PD-1) checkpoint blockade sensitivity <em>in vivo</em>. Importantly, reduced <em>TYW2</em> expression is associated with increased response to checkpoint blockade in patients. Together, we demonstrate that defects in translation fidelity drive tumor immunogenicity and may be leveraged for cancer immunotherapy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"3 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713596","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 : 2025-03-27DOI: 10.1016/j.ccell.2025.03.007
Ioanna Mosialou, Abdullah M. Ali, Rossella Labella, Brygida Bisikirska, Alvaro Cuesta-Dominguez, Paraskevi Vgenopoulou, Ismarc Reyes, Sanjana M. Rao, Anqi Wang, Na Luo, Marta Galan-Diez, Junfei Zhao, Brian J. Chernak, Jan Philipp Bewersdorf, Kazuya Fukasawa, Jiayu Su, Jason Higa, Rachel A. Adams, Adam L. Corper, Sergey Pampou, Stavroula Kousteni
Myeloid cancers such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) remain resistant to standard of care (SOC) and targeted therapies. In this study, we demonstrate that responsiveness to therapy is associated with activation of β-catenin-JAG1 in osteoblastic cells of patients treated with all-trans-retinoic acid (ATRA). ATRA suppresses β-catenin activity in patients and leukemic mice. Consequently, it inhibits the growth and survival of MDS/AML cells from patients with active β-catenin-JAG1 signaling and promotes their differentiation. This occurs independently of cytogenetics and mutational profile. ATRA also improves disease outcome in mice with no evidence of relapse and a superior safety profile to SOC. A human anti-JAG1 antibody improves efficacy in leukemic mice and patient-derived MDS/AML cells. β-catenin activation provides an explanation for the differential response to ATRA and a mechanistic biomarker for ATRA repurposing in myeloid malignancies, potentially evading relapse and extending across a broad range of cancers.
{"title":"A niche driven mechanism determines response and a mutation-independent therapeutic approach for myeloid malignancies","authors":"Ioanna Mosialou, Abdullah M. Ali, Rossella Labella, Brygida Bisikirska, Alvaro Cuesta-Dominguez, Paraskevi Vgenopoulou, Ismarc Reyes, Sanjana M. Rao, Anqi Wang, Na Luo, Marta Galan-Diez, Junfei Zhao, Brian J. Chernak, Jan Philipp Bewersdorf, Kazuya Fukasawa, Jiayu Su, Jason Higa, Rachel A. Adams, Adam L. Corper, Sergey Pampou, Stavroula Kousteni","doi":"10.1016/j.ccell.2025.03.007","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.03.007","url":null,"abstract":"Myeloid cancers such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) remain resistant to standard of care (SOC) and targeted therapies. In this study, we demonstrate that responsiveness to therapy is associated with activation of β-catenin-JAG1 in osteoblastic cells of patients treated with all-<em>trans</em>-retinoic acid (ATRA). ATRA suppresses β-catenin activity in patients and leukemic mice. Consequently, it inhibits the growth and survival of MDS/AML cells from patients with active β-catenin-JAG1 signaling and promotes their differentiation. This occurs independently of cytogenetics and mutational profile. ATRA also improves disease outcome in mice with no evidence of relapse and a superior safety profile to SOC. A human anti-JAG1 antibody improves efficacy in leukemic mice and patient-derived MDS/AML cells. β-catenin activation provides an explanation for the differential response to ATRA and a mechanistic biomarker for ATRA repurposing in myeloid malignancies, potentially evading relapse and extending across a broad range of cancers.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"33 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713602","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 : 2025-03-27DOI: 10.1016/j.ccell.2025.03.010
Pedro R. Lowenstein, Maria Luisa Varela, Maria G. Castro
Oncolytic viruses (OVs) are being optimized to treat cancer, including brain, ovarian, lung, and pancreatic tumors. Recent advances include replicating adenoviruses and herpes simplex virus 1 (HSV-1) armed with therapeutic transgenes, combined with serial injections and systemic delivery via retargeting, as achieved for adeno-associated virus 9 (AAV9). Clinical trials are showing promising efficacy. Here, we summarize the advancements and challenges associated with OV-based cancer therapies and discuss their mechanisms of action and strategies for enhancing the efficacy of OV treatments.
{"title":"The discrete charm of oncolytic viruses: Toward the finish line","authors":"Pedro R. Lowenstein, Maria Luisa Varela, Maria G. Castro","doi":"10.1016/j.ccell.2025.03.010","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.03.010","url":null,"abstract":"Oncolytic viruses (OVs) are being optimized to treat cancer, including brain, ovarian, lung, and pancreatic tumors. Recent advances include replicating adenoviruses and herpes simplex virus 1 (HSV-1) armed with therapeutic transgenes, combined with serial injections and systemic delivery via retargeting, as achieved for adeno-associated virus 9 (AAV9). Clinical trials are showing promising efficacy. Here, we summarize the advancements and challenges associated with OV-based cancer therapies and discuss their mechanisms of action and strategies for enhancing the efficacy of OV treatments.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"61 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713599","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 : 2025-03-27DOI: 10.1016/j.ccell.2025.03.008
Usama-Ur Rehman, Michael Lübbert
All-trans retinoic acid (ATRA), a known regulator of hematopoiesis, is a key component of the established therapeutic regimen for treating acute promyelocytic leukemia (APL). In this issue of Cancer Cell, Mosialou et al. present a niche-based mechanism of ATRA targeting osteoblasts, repurposing ATRA treatment beyond APL.
{"title":"All-trans retinoic acid beyond acute promyelocytic leukemia","authors":"Usama-Ur Rehman, Michael Lübbert","doi":"10.1016/j.ccell.2025.03.008","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.03.008","url":null,"abstract":"All-<em>trans</em> retinoic acid (ATRA), a known regulator of hematopoiesis, is a key component of the established therapeutic regimen for treating acute promyelocytic leukemia (APL). In this issue of <em>Cancer Cell</em>, Mosialou et al. present a niche-based mechanism of ATRA targeting osteoblasts, repurposing ATRA treatment beyond APL.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"72 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713802","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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