Pub Date : 2024-03-27DOI: 10.1038/s43018-024-00735-y
Hans R. Widlund, Lydia Lynch
Identifying which patients will benefit most from immune checkpoint blockade (ICB) is an important clinical challenge. A study now finds that Vδ1+ γδ T cells are associated with better response to ICB in melanoma tumors with a lower neoantigen load and shows that some effector functions of PD-1+ Vδ1+ T cells are repressed after engagement of PD-1 by PD-L1.
{"title":"γδ T cells as unconventional targets of checkpoint blockade","authors":"Hans R. Widlund, Lydia Lynch","doi":"10.1038/s43018-024-00735-y","DOIUrl":"10.1038/s43018-024-00735-y","url":null,"abstract":"Identifying which patients will benefit most from immune checkpoint blockade (ICB) is an important clinical challenge. A study now finds that Vδ1+ γδ T cells are associated with better response to ICB in melanoma tumors with a lower neoantigen load and shows that some effector functions of PD-1+ Vδ1+ T cells are repressed after engagement of PD-1 by PD-L1.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":22.7,"publicationDate":"2024-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140306272","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 : 2024-03-27DOI: 10.1038/s43018-023-00708-7
Laura Leonhardt, Matthias Hebrok
Effectively targeting deregulated KRAS signaling remains an unmet clinical need, as current approaches commonly lead to the development of chemoresistance in clinical settings. ADAM9-mediated lysosomal KRAS degradation is now shown to counteract PDAC chemoresistance independently of mutational status.
{"title":"KRAS degradation averts PDAC chemoresistance","authors":"Laura Leonhardt, Matthias Hebrok","doi":"10.1038/s43018-023-00708-7","DOIUrl":"10.1038/s43018-023-00708-7","url":null,"abstract":"Effectively targeting deregulated KRAS signaling remains an unmet clinical need, as current approaches commonly lead to the development of chemoresistance in clinical settings. ADAM9-mediated lysosomal KRAS degradation is now shown to counteract PDAC chemoresistance independently of mutational status.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":22.7,"publicationDate":"2024-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140306271","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 : 2024-03-25DOI: 10.1038/s43018-024-00752-x
Maishara Muquith, Magdalena Espinoza, Andrew Elliott, Joanne Xiu, Andreas Seeber, Wafik El-Deiry, Emmanuel S. Antonarakis, Stephanie L. Graff, Michael J. Hall, Hossein Borghaei, Dave S. B. Hoon, Stephen V. Liu, Patrick C. Ma, Rana R. McKay, Trisha Wise-Draper, John Marshall, George W. Sledge, David Spetzler, Hao Zhu, David Hsiehchen
Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 or its ligand (PD-1/L1) have expanded the treatment landscape against cancers but are effective in only a subset of patients. Tumor mutation burden (TMB) is postulated to be a generic determinant of ICI-dependent tumor rejection. Here we describe the association between TMB and survival outcomes among microsatellite-stable cancers in a real-world clinicogenomic cohort consisting of 70,698 patients distributed across 27 histologies. TMB was associated with survival benefit or detriment depending on tissue and treatment context, with eight cancer types demonstrating a specific association between TMB and improved outcomes upon treatment with anti-PD-1/L1 therapies. Survival benefits were noted over a broad range of TMB cutoffs across cancer types, and a dose-dependent relationship between TMB and outcomes was observed in a subset of cancers. These results have implications for the use of cancer-agnostic and universal TMB cutoffs to guide the use of anti-PD-1/L1 therapies, and they underline the importance of tissue context in the development of ICI biomarkers. Hsiehchen and colleagues assess the association between tumor mutational burden and survival in a real-world cohort of patients with microsatellite-stable cancers.
{"title":"Tissue-specific thresholds of mutation burden associated with anti-PD-1/L1 therapy benefit and prognosis in microsatellite-stable cancers","authors":"Maishara Muquith, Magdalena Espinoza, Andrew Elliott, Joanne Xiu, Andreas Seeber, Wafik El-Deiry, Emmanuel S. Antonarakis, Stephanie L. Graff, Michael J. Hall, Hossein Borghaei, Dave S. B. Hoon, Stephen V. Liu, Patrick C. Ma, Rana R. McKay, Trisha Wise-Draper, John Marshall, George W. Sledge, David Spetzler, Hao Zhu, David Hsiehchen","doi":"10.1038/s43018-024-00752-x","DOIUrl":"10.1038/s43018-024-00752-x","url":null,"abstract":"Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 or its ligand (PD-1/L1) have expanded the treatment landscape against cancers but are effective in only a subset of patients. Tumor mutation burden (TMB) is postulated to be a generic determinant of ICI-dependent tumor rejection. Here we describe the association between TMB and survival outcomes among microsatellite-stable cancers in a real-world clinicogenomic cohort consisting of 70,698 patients distributed across 27 histologies. TMB was associated with survival benefit or detriment depending on tissue and treatment context, with eight cancer types demonstrating a specific association between TMB and improved outcomes upon treatment with anti-PD-1/L1 therapies. Survival benefits were noted over a broad range of TMB cutoffs across cancer types, and a dose-dependent relationship between TMB and outcomes was observed in a subset of cancers. These results have implications for the use of cancer-agnostic and universal TMB cutoffs to guide the use of anti-PD-1/L1 therapies, and they underline the importance of tissue context in the development of ICI biomarkers. Hsiehchen and colleagues assess the association between tumor mutational burden and survival in a real-world cohort of patients with microsatellite-stable cancers.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140288508","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 : 2024-03-22DOI: 10.1038/s43018-024-00747-8
Johanna A. Joyce
Johanna Joyce received her PhD from the University of Cambridge, and did postdoctoral research at the University of California, San Francisco. She then joined the faculty at Memorial Sloan Kettering Cancer Center, New York, becoming a tenured member in 2014. She moved to Switzerland in 2016, where she later served as the inaugural executive director of the Agora Cancer Center Lausanne. She is currently a member of the Ludwig Institute for Cancer Research and a professor at the University of Lausanne.
Johanna Joyce 在剑桥大学获得博士学位，并在加州大学旧金山分校从事博士后研究。随后，她加入纽约斯隆-凯特琳纪念癌症中心任教，并于2014年成为终身教职员工。她于2016年移居瑞士，随后担任洛桑Agora癌症中心的首任执行主任。目前，她是路德维希癌症研究所成员和洛桑大学教授。
{"title":"Trans-Atlantic twists and turns","authors":"Johanna A. Joyce","doi":"10.1038/s43018-024-00747-8","DOIUrl":"10.1038/s43018-024-00747-8","url":null,"abstract":"Johanna Joyce received her PhD from the University of Cambridge, and did postdoctoral research at the University of California, San Francisco. She then joined the faculty at Memorial Sloan Kettering Cancer Center, New York, becoming a tenured member in 2014. She moved to Switzerland in 2016, where she later served as the inaugural executive director of the Agora Cancer Center Lausanne. She is currently a member of the Ludwig Institute for Cancer Research and a professor at the University of Lausanne.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":22.7,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140194215","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 : 2024-03-22DOI: 10.1038/s43018-024-00738-9
Katherine Wu, Ahmed Ezat El Zowalaty, Volkan I. Sayin, Thales Papagiannakopoulos
Cellular redox homeostasis is an essential, dynamic process that ensures the balance between reducing and oxidizing reactions within cells and thus has implications across all areas of biology. Changes in levels of reactive oxygen species can disrupt redox homeostasis, leading to oxidative or reductive stress that contributes to the pathogenesis of many malignancies, including cancer. From transformation and tumor initiation to metastatic dissemination, increasing reactive oxygen species in cancer cells can paradoxically promote or suppress the tumorigenic process, depending on the extent of redox stress, its spatiotemporal characteristics and the tumor microenvironment. Here we review how redox regulation influences tumorigenesis, highlighting therapeutic opportunities enabled by redox-related alterations in cancer cells. Papagiannakopoulos and colleagues discuss the roles of reactive oxygen species in cancer and the ways in which redox mechanisms may be exploited for cancer therapy.
{"title":"The pleiotropic functions of reactive oxygen species in cancer","authors":"Katherine Wu, Ahmed Ezat El Zowalaty, Volkan I. Sayin, Thales Papagiannakopoulos","doi":"10.1038/s43018-024-00738-9","DOIUrl":"10.1038/s43018-024-00738-9","url":null,"abstract":"Cellular redox homeostasis is an essential, dynamic process that ensures the balance between reducing and oxidizing reactions within cells and thus has implications across all areas of biology. Changes in levels of reactive oxygen species can disrupt redox homeostasis, leading to oxidative or reductive stress that contributes to the pathogenesis of many malignancies, including cancer. From transformation and tumor initiation to metastatic dissemination, increasing reactive oxygen species in cancer cells can paradoxically promote or suppress the tumorigenic process, depending on the extent of redox stress, its spatiotemporal characteristics and the tumor microenvironment. Here we review how redox regulation influences tumorigenesis, highlighting therapeutic opportunities enabled by redox-related alterations in cancer cells. Papagiannakopoulos and colleagues discuss the roles of reactive oxygen species in cancer and the ways in which redox mechanisms may be exploited for cancer therapy.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":22.7,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140203438","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 : 2024-03-22DOI: 10.1038/s43018-024-00748-7
Xujia Wu, Huairui Yuan, Qiulian Wu, Yixin Gao, Tingting Duan, Kailin Yang, Tengfei Huang, Shuai Wang, Fanen Yuan, Derrick Lee, Suchet Taori, Tritan Plute, Søren Heissel, Hanan Alwaseem, Michael Isay-Del Viscio, Henrik Molina, Sameer Agnihotri, Dennis J. Hsu, Nu Zhang, Jeremy N. Rich
Cancers commonly reprogram translation and metabolism, but little is known about how these two features coordinate in cancer stem cells. Here we show that glioblastoma stem cells (GSCs) display elevated protein translation. To dissect underlying mechanisms, we performed a CRISPR screen and identified YRDC as the top essential transfer RNA (tRNA) modification enzyme in GSCs. YRDC catalyzes the formation of N6-threonylcarbamoyladenosine (t6A) on ANN-decoding tRNA species (A denotes adenosine, and N denotes any nucleotide). Targeting YRDC reduced t6A formation, suppressed global translation and inhibited tumor growth both in vitro and in vivo. Threonine is an essential substrate of YRDC. Threonine accumulated in GSCs, which facilitated t6A formation through YRDC and shifted the proteome to support mitosis-related genes with ANN codon bias. Dietary threonine restriction (TR) reduced tumor t6A formation, slowed xenograft growth and augmented anti-tumor efficacy of chemotherapy and anti-mitotic therapy, providing a molecular basis for a dietary intervention in cancer treatment. Rich and colleagues show that glioblastoma stem cells have increased global protein translation, which is achieved via the tRNA modifier YRDC. They show that targeting it or reducing its substrate threonine suppresses tumor growth.
{"title":"Threonine fuels glioblastoma through YRDC-mediated codon-biased translational reprogramming","authors":"Xujia Wu, Huairui Yuan, Qiulian Wu, Yixin Gao, Tingting Duan, Kailin Yang, Tengfei Huang, Shuai Wang, Fanen Yuan, Derrick Lee, Suchet Taori, Tritan Plute, Søren Heissel, Hanan Alwaseem, Michael Isay-Del Viscio, Henrik Molina, Sameer Agnihotri, Dennis J. Hsu, Nu Zhang, Jeremy N. Rich","doi":"10.1038/s43018-024-00748-7","DOIUrl":"10.1038/s43018-024-00748-7","url":null,"abstract":"Cancers commonly reprogram translation and metabolism, but little is known about how these two features coordinate in cancer stem cells. Here we show that glioblastoma stem cells (GSCs) display elevated protein translation. To dissect underlying mechanisms, we performed a CRISPR screen and identified YRDC as the top essential transfer RNA (tRNA) modification enzyme in GSCs. YRDC catalyzes the formation of N6-threonylcarbamoyladenosine (t6A) on ANN-decoding tRNA species (A denotes adenosine, and N denotes any nucleotide). Targeting YRDC reduced t6A formation, suppressed global translation and inhibited tumor growth both in vitro and in vivo. Threonine is an essential substrate of YRDC. Threonine accumulated in GSCs, which facilitated t6A formation through YRDC and shifted the proteome to support mitosis-related genes with ANN codon bias. Dietary threonine restriction (TR) reduced tumor t6A formation, slowed xenograft growth and augmented anti-tumor efficacy of chemotherapy and anti-mitotic therapy, providing a molecular basis for a dietary intervention in cancer treatment. Rich and colleagues show that glioblastoma stem cells have increased global protein translation, which is achieved via the tRNA modifier YRDC. They show that targeting it or reducing its substrate threonine suppresses tumor growth.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140194214","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 : 2024-03-19DOI: 10.1038/s43018-024-00744-x
Anton Dobrin, Pieter L. Lindenbergh, Yuzhe Shi, Karlo Perica, Hongyao Xie, Nayan Jain, Andrew Chow, Jedd D. Wolchok, Taha Merghoub, Michel Sadelain, Mohamad Hamieh
Chimeric antigen receptor T cells have dramatically improved the treatment of hematologic malignancies. T cell antigen receptor (TCR)-based cell therapies are yet to achieve comparable outcomes. Importantly, chimeric antigen receptors not only target selected antigens but also reprogram T cell functions through the co-stimulatory pathways that they engage upon antigen recognition. We show here that a fusion receptor comprising the CD80 ectodomain and the 4-1BB cytoplasmic domain, termed 80BB, acts as both a ligand and a receptor to engage the CD28 and 4-1BB pathways, thereby increasing the antitumor potency of human leukocyte antigen-independent TCR (HIT) receptor- or TCR-engineered T cells and tumor-infiltrating lymphocytes. Furthermore, 80BB serves as a switch receptor that provides agonistic 4-1BB co-stimulation upon its ligation by the inhibitory CTLA4 molecule. By combining multiple co-stimulatory features in a single antigen-agnostic synthetic receptor, 80BB is a promising tool to sustain CD3-dependent T cell responses in a wide range of targeted immunotherapies. Dobrin et al. develop a fusion receptor comprising the CD80 ectodomain and the 4-1BB cytoplasmic domain, which engages the CD28 and 4-1BB pathways and increases the antitumor potency of HLA-independent (HIT) and TCR-engineered T cells.
嵌合抗原受体 T 细胞大大改善了血液恶性肿瘤的治疗。基于T细胞抗原受体（TCR）的细胞疗法尚未取得可比的疗效。重要的是，嵌合抗原受体不仅能靶向选定的抗原，还能通过它们在识别抗原时参与的共刺激通路重编程 T 细胞功能。我们在这里展示了一种由CD80外结构域和4-1BB胞质结构域组成的融合受体（称为80BB），它既是配体又是受体，可参与CD28和4-1BB途径，从而提高人类白细胞抗原无关的TCR（HIT）受体或TCR工程T细胞和肿瘤浸润淋巴细胞的抗肿瘤效力。此外，80BB 还是一种开关受体，当它与抑制性 CTLA4 分子连接时，可提供激动性 4-1BB 协同刺激。80BB 在单一抗原识别合成受体中结合了多种协同刺激功能，是在多种靶向免疫疗法中维持 CD3 依赖性 T 细胞反应的一种很有前途的工具。
{"title":"Synthetic dual co-stimulation increases the potency of HIT and TCR-targeted cell therapies","authors":"Anton Dobrin, Pieter L. Lindenbergh, Yuzhe Shi, Karlo Perica, Hongyao Xie, Nayan Jain, Andrew Chow, Jedd D. Wolchok, Taha Merghoub, Michel Sadelain, Mohamad Hamieh","doi":"10.1038/s43018-024-00744-x","DOIUrl":"10.1038/s43018-024-00744-x","url":null,"abstract":"Chimeric antigen receptor T cells have dramatically improved the treatment of hematologic malignancies. T cell antigen receptor (TCR)-based cell therapies are yet to achieve comparable outcomes. Importantly, chimeric antigen receptors not only target selected antigens but also reprogram T cell functions through the co-stimulatory pathways that they engage upon antigen recognition. We show here that a fusion receptor comprising the CD80 ectodomain and the 4-1BB cytoplasmic domain, termed 80BB, acts as both a ligand and a receptor to engage the CD28 and 4-1BB pathways, thereby increasing the antitumor potency of human leukocyte antigen-independent TCR (HIT) receptor- or TCR-engineered T cells and tumor-infiltrating lymphocytes. Furthermore, 80BB serves as a switch receptor that provides agonistic 4-1BB co-stimulation upon its ligation by the inhibitory CTLA4 molecule. By combining multiple co-stimulatory features in a single antigen-agnostic synthetic receptor, 80BB is a promising tool to sustain CD3-dependent T cell responses in a wide range of targeted immunotherapies. Dobrin et al. develop a fusion receptor comprising the CD80 ectodomain and the 4-1BB cytoplasmic domain, which engages the CD28 and 4-1BB pathways and increases the antitumor potency of HLA-independent (HIT) and TCR-engineered T cells.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":22.7,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140170424","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 : 2024-03-12DOI: 10.1038/s43018-024-00751-y
Yuliana Astuti, Meirion Raymant, Valeria Quaranta, Kim Clarke, Maidinaimu Abudula, Olivia Smith, Gaia Bellomo, Vatshala Chandran-Gorner, Craig Nourse, Christopher Halloran, Paula Ghaneh, Daniel Palmer, Robert P. Jones, Fiona Campbell, Jeffrey W. Pollard, Jennifer P. Morton, Ainhoa Mielgo, Michael C. Schmid
{"title":"Author Correction: Efferocytosis reprograms the tumor microenvironment to promote pancreatic cancer liver metastasis","authors":"Yuliana Astuti, Meirion Raymant, Valeria Quaranta, Kim Clarke, Maidinaimu Abudula, Olivia Smith, Gaia Bellomo, Vatshala Chandran-Gorner, Craig Nourse, Christopher Halloran, Paula Ghaneh, Daniel Palmer, Robert P. Jones, Fiona Campbell, Jeffrey W. Pollard, Jennifer P. Morton, Ainhoa Mielgo, Michael C. Schmid","doi":"10.1038/s43018-024-00751-y","DOIUrl":"10.1038/s43018-024-00751-y","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":22.7,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43018-024-00751-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140110684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-06DOI: 10.1038/s43018-024-00742-z
Tajinder Ubhi, Olga Zaslaver, Andrew T. Quaile, Dennis Plenker, Pinjiang Cao, Nhu-An Pham, Angéla Békési, Gun-Ho Jang, Grainne M. O’Kane, Faiyaz Notta, Jason Moffat, Julie M. Wilson, Steven Gallinger, Beáta G. Vértessy, David A. Tuveson, Hannes L. Röst, Grant W. Brown
Gemcitabine is a potent inhibitor of DNA replication and is a mainstay therapeutic for diverse cancers, particularly pancreatic ductal adenocarcinoma (PDAC). However, most tumors remain refractory to gemcitabine therapies. Here, to define the cancer cell response to gemcitabine, we performed genome-scale CRISPR–Cas9 chemical–genetic screens in PDAC cells and found selective loss of cell fitness upon disruption of the cytidine deaminases APOBEC3C and APOBEC3D. Following gemcitabine treatment, APOBEC3C and APOBEC3D promote DNA replication stress resistance and cell survival by deaminating cytidines in the nuclear genome to ensure DNA replication fork restart and repair in PDAC cells. We provide evidence that the chemical–genetic interaction between APOBEC3C or APOBEC3D and gemcitabine is absent in nontransformed cells but is recapitulated across different PDAC cell lines, in PDAC organoids and in PDAC xenografts. Thus, we uncover roles for APOBEC3C and APOBEC3D in DNA replication stress resistance and offer plausible targets for improving gemcitabine-based therapies for PDAC. Ubhi et al. describe the contribution of APOBEC family members A3C and A3D in the gemcitabine resistance mechanism in the context of pancreatic cancer, which is mediated by facilitating the restart of treatment-induced stalled replication forks.
吉西他滨是一种强效的DNA复制抑制剂，是治疗各种癌症，尤其是胰腺导管腺癌（PDAC）的主流疗法。然而，大多数肿瘤仍对吉西他滨疗法难治。在这里，为了确定癌细胞对吉西他滨的反应，我们在PDAC细胞中进行了基因组规模的CRISPR-Cas9化学遗传筛选，发现细胞苷脱氨酶APOBEC3C和APOBEC3D被破坏后，细胞的适应性会发生选择性丧失。在吉西他滨治疗后，APOBEC3C 和 APOBEC3D 通过对核基因组中的胞嘧啶进行脱氨来确保 PDAC 细胞中 DNA 复制叉的重启和修复，从而促进 DNA 复制应激抗性和细胞存活。我们提供的证据表明，APOBEC3C 或 APOBEC3D 与吉西他滨之间的化学-遗传相互作用在未转化细胞中不存在，但在不同的 PDAC 细胞系、PDAC 有机体和 PDAC 异种移植物中都能重现。因此，我们发现了 APOBEC3C 和 APOBEC3D 在 DNA 复制应激抗性中的作用，并为改进基于吉西他滨的 PDAC 疗法提供了可信的靶点。
{"title":"Cytidine deaminases APOBEC3C and APOBEC3D promote DNA replication stress resistance in pancreatic cancer cells","authors":"Tajinder Ubhi, Olga Zaslaver, Andrew T. Quaile, Dennis Plenker, Pinjiang Cao, Nhu-An Pham, Angéla Békési, Gun-Ho Jang, Grainne M. O’Kane, Faiyaz Notta, Jason Moffat, Julie M. Wilson, Steven Gallinger, Beáta G. Vértessy, David A. Tuveson, Hannes L. Röst, Grant W. Brown","doi":"10.1038/s43018-024-00742-z","DOIUrl":"10.1038/s43018-024-00742-z","url":null,"abstract":"Gemcitabine is a potent inhibitor of DNA replication and is a mainstay therapeutic for diverse cancers, particularly pancreatic ductal adenocarcinoma (PDAC). However, most tumors remain refractory to gemcitabine therapies. Here, to define the cancer cell response to gemcitabine, we performed genome-scale CRISPR–Cas9 chemical–genetic screens in PDAC cells and found selective loss of cell fitness upon disruption of the cytidine deaminases APOBEC3C and APOBEC3D. Following gemcitabine treatment, APOBEC3C and APOBEC3D promote DNA replication stress resistance and cell survival by deaminating cytidines in the nuclear genome to ensure DNA replication fork restart and repair in PDAC cells. We provide evidence that the chemical–genetic interaction between APOBEC3C or APOBEC3D and gemcitabine is absent in nontransformed cells but is recapitulated across different PDAC cell lines, in PDAC organoids and in PDAC xenografts. Thus, we uncover roles for APOBEC3C and APOBEC3D in DNA replication stress resistance and offer plausible targets for improving gemcitabine-based therapies for PDAC. Ubhi et al. describe the contribution of APOBEC family members A3C and A3D in the gemcitabine resistance mechanism in the context of pancreatic cancer, which is mediated by facilitating the restart of treatment-induced stalled replication forks.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140049937","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 : 2024-03-05DOI: 10.1038/s43018-024-00740-1
Sungjoon Park, Erica Silva, Akshat Singhal, Marcus R. Kelly, Kate Licon, Isabella Panagiotou, Catalina Fogg, Samson Fong, John J. Y. Lee, Xiaoyu Zhao, Robin Bachelder, Barbara A. Parker, Kay T. Yeung, Trey Ideker
Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have revolutionized breast cancer therapy. However, <50% of patients have an objective response, and nearly all patients develop resistance during therapy. To elucidate the underlying mechanisms, we constructed an interpretable deep learning model of the response to palbociclib, a CDK4/6i, based on a reference map of multiprotein assemblies in cancer. The model identifies eight core assemblies that integrate rare and common alterations across 90 genes to stratify palbociclib-sensitive versus palbociclib-resistant cell lines. Predictions translate to patients and patient-derived xenografts, whereas single-gene biomarkers do not. Most predictive assemblies can be shown by CRISPR–Cas9 genetic disruption to regulate the CDK4/6i response. Validated assemblies relate to cell-cycle control, growth factor signaling and a histone regulatory complex that we show promotes S-phase entry through the activation of the histone modifiers KAT6A and TBL1XR1 and the transcription factor RUNX1. This study enables an integrated assessment of how a tumor’s genetic profile modulates CDK4/6i resistance. Ideker and colleagues present NeST-VVN, a deep learning model based on cancer protein assembly data that can be used to predict the response and resistance of cancer cells to CDK4/6 inhibitors.
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