Genes & development最新文献

Genetics and biology of pancreatic ductal adenocarcinoma 胰腺导管腺癌的遗传学和生物学特性

IF 10.5 1区生物学

Genes & development Pub Date : 2024-11-07 DOI: 10.1101/gad.351863.124

Haoqiang Ying, Alec C. Kimmelman, Nabeel Bardeesy, Raghu Kalluri, Anirban Maitra, Ronald A. DePinho

{"title":"Genetics and biology of pancreatic ductal adenocarcinoma","authors":"Haoqiang Ying, Alec C. Kimmelman, Nabeel Bardeesy, Raghu Kalluri, Anirban Maitra, Ronald A. DePinho","doi":"10.1101/gad.351863.124","DOIUrl":"https://doi.org/10.1101/gad.351863.124","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) poses a grim prognosis for patients. Recent multidisciplinary research efforts have provided critical insights into its genetics and tumor biology, creating the foundation for rational development of targeted and immune therapies. Here, we review the PDAC genomic landscape and the role of specific oncogenic events in tumor initiation and progression, as well as their contributions to shaping its tumor biology. We further summarize and synthesize breakthroughs in single-cell and metabolic profiling technologies that have illuminated the complex cellular composition and heterotypic interactions of the PDAC tumor microenvironment, with an emphasis on metabolic cross-talk across cancer and stromal cells that sustains anabolic growth and suppresses tumor immunity. These conceptual advances have generated novel immunotherapy regimens, particularly cancer vaccines, which are now in clinical testing. We also highlight the advent of KRAS targeted therapy, a milestone advance that has transformed treatment paradigms and offers a platform for combined immunotherapy and targeted strategies. This review provides a perspective summarizing current scientific and therapeutic challenges as well as practice-changing opportunities for the PDAC field at this major inflection point.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

BRCA1 and BRCA2: from cancer susceptibility to synthetic lethality BRCA1 和 BRCA2：从癌症易感性到合成致死性

IF 10.5 1区生物学

Genes & development Pub Date : 2024-11-07 DOI: 10.1101/gad.352083.124

Anna Khalizieva, Sarah C. Moser, Peter Bouwman, Jos Jonkers

引用次数: 0

Classifying the molecular functions of transcription factors beyond activation and repression. 对转录因子的分子功能进行分类，而不仅仅是激活和抑制。

IF 7.5 1区生物学

Genes & development Pub Date : 2024-11-06 DOI: 10.1101/gad.352340.124

Jinhong Dong, Michael J Guertin

引用次数: 0

Deciphering normal and cancer stem cell niches by spatial transcriptomics: opportunities and challenges. 通过空间转录组学解读正常和癌症干细胞龛位：机遇与挑战。

IF 7.5 1区生物学

Genes & development Pub Date : 2024-11-04 DOI: 10.1101/gad.351956.124

Hirak Sarkar, Eunmi Lee, Sereno L Lopez-Darwin, Yibin Kang

{"title":"Deciphering normal and cancer stem cell niches by spatial transcriptomics: opportunities and challenges.","authors":"Hirak Sarkar, Eunmi Lee, Sereno L Lopez-Darwin, Yibin Kang","doi":"10.1101/gad.351956.124","DOIUrl":"https://doi.org/10.1101/gad.351956.124","url":null,"abstract":"Cancer stem cells (CSCs) often exhibit stem-like attributes that depend on an intricate stemness-promoting cellular ecosystem within their niche. The interplay between CSCs and their niche has been implicated in tumor heterogeneity and therapeutic resistance. Normal stem cells (NSCs) and CSCs share stemness features and common microenvironmental components, displaying significant phenotypic and functional plasticity. Investigating these properties across diverse organs during normal development and tumorigenesis is of paramount research interest and translational potential. Advancements in next-generation sequencing (NGS), single-cell transcriptomics, and spatial transcriptomics have ushered in a new era in cancer research, providing high-resolution and comprehensive molecular maps of diseased tissues. Various spatial technologies, with their unique ability to measure the location and molecular profile of a cell within tissue, have enabled studies on intratumoral architecture and cellular cross-talk within the specific niches. Moreover, delineation of spatial patterns for niche-specific properties such as hypoxia, glucose deprivation, and other microenvironmental remodeling are revealed through multilevel spatial sequencing. This tremendous progress in technology has also been paired with the advent of computational tools to mitigate technology-specific bottlenecks. Here we discuss how different spatial technologies are used to identify NSCs and CSCs, as well as their associated niches. Additionally, by exploring related public data sets, we review the current challenges in characterizing such niches, which are often hindered by technological limitations, and the computational solutions used to address them.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DNA-directed termination of mammalian RNA polymerase II 哺乳动物 RNA 聚合酶 II 的 DNA 定向终止

IF 10.5 1区生物学

Genes & development Pub Date : 2024-11-04 DOI: 10.1101/gad.351978.124

Lee Davidson, Jérôme O. Rouvière, Rui Sousa-Luís, Takayuki Nojima, Nicholas J. Proudfoot, Torben Heick Jensen, Steven West

{"title":"DNA-directed termination of mammalian RNA polymerase II","authors":"Lee Davidson, Jérôme O. Rouvière, Rui Sousa-Luís, Takayuki Nojima, Nicholas J. Proudfoot, Torben Heick Jensen, Steven West","doi":"10.1101/gad.351978.124","DOIUrl":"https://doi.org/10.1101/gad.351978.124","url":null,"abstract":"The best-studied mechanism of eukaryotic RNA polymerase II (RNAPII) transcriptional termination involves polyadenylation site-directed cleavage of the nascent RNA. The RNAPII-associated cleavage product is then degraded by XRN2, dislodging RNAPII from the DNA template. In contrast, prokaryotic RNAP and eukaryotic RNAPIII often terminate directly at T-tracts in the coding DNA strand. Here, we demonstrate a similar and omnipresent capability for mammalian RNAPII. Importantly, this termination mechanism does not require upstream RNA cleavage. Accordingly, T-tract-dependent termination can take place when XRN2 cannot be engaged. We show that T-tracts can terminate snRNA transcription independently of RNA cleavage by the Integrator complex. Importantly, we found genome-wide termination at T-tracts in promoter-proximal regions but not within protein-coding gene bodies. XRN2-dependent termination dominates downstream from protein-coding genes, but the T-tract process is sometimes used. Overall, we demonstrate global DNA-directed attrition of RNAPII transcription, suggesting that RNAPs retain the potential to terminate over T-rich sequences throughout evolution.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Molecular and cellular dynamics of squamous cell carcinomas across tissues 不同组织鳞状细胞癌的分子和细胞动态变化

IF 10.5 1区生物学

Genes & development Pub Date : 2024-10-25 DOI: 10.1101/gad.351990.124

Matthew R. Kudelka, Yonit Lavin, Siman Sun, Elaine Fuchs

引用次数: 0

Chronic interferon-stimulated gene transcription promotes oncogene-induced breast cancer 慢性干扰素刺激基因转录促进癌基因诱发乳腺癌

IF 10.5 1区生物学

Genes & development Pub Date : 2024-10-25 DOI: 10.1101/gad.351455.123

Hexiao Wang, Claudia Canasto-Chibuque, Jun Hyun Kim, Marcel Hohl, Christina Leslie, Jorge S. Reis-Filho, John H.J. Petrini

{"title":"Chronic interferon-stimulated gene transcription promotes oncogene-induced breast cancer","authors":"Hexiao Wang, Claudia Canasto-Chibuque, Jun Hyun Kim, Marcel Hohl, Christina Leslie, Jorge S. Reis-Filho, John H.J. Petrini","doi":"10.1101/gad.351455.123","DOIUrl":"https://doi.org/10.1101/gad.351455.123","url":null,"abstract":"The MRE11 complex (comprising MRE11, RAD50, and NBS1) is integral to the maintenance of genome stability. We previously showed that a hypomorphic Mre11 mutant mouse strain (Mre11ATLD1/ATLD1) was highly susceptible to oncogene-induced breast cancer. Here we used a mammary organoid system to examine which MRE11-dependent responses are tumor-suppressive. We found that Mre11ATLD1/ATLD1 organoids exhibited an elevated interferon-stimulated gene (ISG) signature and sustained changes in chromatin accessibility. This Mre11ATLD1/ATLD1 phenotype depended on DNA binding of a nuclear innate immune sensor, IFI205. Ablation of Ifi205 in Mre11ATLD1/ATLD1 organoids restored baseline and oncogene-induced chromatin accessibility patterns to those observed in WT. Implantation of Mre11ATLD1/ATLD1 organoids and activation of the oncogene led to aggressive metastatic breast cancer. This outcome was reversed in implanted Ifi205−/− Mre11ATLD1/ATLD1 organoids. These data reveal a connection between innate immune signaling and tumor development in the mammary epithelium. Given the abundance of aberrant DNA structures that arise in the context of genome instability syndromes, the data further suggest that cancer predisposition in those contexts may be partially attributable to chronic innate immune transcriptional programs.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Circadian de(regulation) in physiology: implications for disease and treatment 生理学中的昼夜节律调节：对疾病和治疗的影响

IF 10.5 1区生物学

Genes & development Pub Date : 2024-10-17 DOI: 10.1101/gad.352180.124

Leonardo Vinicius Monteiro de Assis, Achim Kramer

{"title":"Circadian de(regulation) in physiology: implications for disease and treatment","authors":"Leonardo Vinicius Monteiro de Assis, Achim Kramer","doi":"10.1101/gad.352180.124","DOIUrl":"https://doi.org/10.1101/gad.352180.124","url":null,"abstract":"Time plays a crucial role in the regulation of physiological processes. Without a temporal control system, animals would be unprepared for cyclic environmental changes, negatively impacting their survival. Experimental studies have demonstrated the essential role of the circadian system in the temporal coordination of physiological processes. Translating these findings to humans has been challenging. Increasing evidence suggests that modern lifestyle factors such as diet, sedentarism, light exposure, and social jet lag can stress the human circadian system, contributing to misalignment; i.e., loss of phase coherence across tissues. An increasing body of evidence supports the negative impact of circadian disruption on several human health parameters. This review aims to provide a comprehensive overview of how circadian disruption influences various physiological processes, its long-term health consequences, and its association with various diseases. To illustrate the relevant consequences of circadian disruption, we focused on describing the many physiological consequences faced by shift workers, a population known to experience high levels of circadian disruption. We also discuss the emerging field of circadian medicine, its founding principles, and its potential impact on human health.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

YY1 knockout in pro-B cells impairs lineage commitment, enabling unusual hematopoietic lineage plasticity. 原 B 细胞中的 YY1 基因敲除会损害血系承诺，从而使造血血系具有不寻常的可塑性。

IF 7.5 1区生物学

Genes & development Pub Date : 2024-10-16 DOI: 10.1101/gad.351734.124

Sarmistha Banerjee, Sulagna Sanyal, Suchita Hodawadekar, Sarah Naiyer, Nasreen Bano, Anupam Banerjee, Joshua Rhoades, Dawei Dong, David Allman, Michael L Atchison

{"title":"YY1 knockout in pro-B cells impairs lineage commitment, enabling unusual hematopoietic lineage plasticity.","authors":"Sarmistha Banerjee, Sulagna Sanyal, Suchita Hodawadekar, Sarah Naiyer, Nasreen Bano, Anupam Banerjee, Joshua Rhoades, Dawei Dong, David Allman, Michael L Atchison","doi":"10.1101/gad.351734.124","DOIUrl":"10.1101/gad.351734.124","url":null,"abstract":"During B-cell development, cells progress through multiple developmental stages, with the pro-B-cell stage defining commitment to the B-cell lineage. YY1 is a ubiquitous transcription factor that is capable of both activation and repression functions. We found here that knockout of YY1 at the pro-B-cell stage eliminates B lineage commitment. YY1 knockout pro-B cells can generate T lineage cells in vitro using the OP9-DL4 feeder system and in vivo after injection into sublethally irradiated Rag1-/- mice. These T lineage-like cells lose their B lineage transcript profile and gain a T-cell lineage profile. Single-cell RNA-seq experiments showed that as YY1 knockout pro-B cells transition into T lineage cells in vitro, various cell clusters adopt transcript profiles representing a multiplicity of hematopoietic lineages, indicating unusual lineage plasticity. In addition, YY1 KO pro-B cells in vivo can give rise to other hematopoietic lineages in vivo. Evaluation of RNA-seq, scRNA-seq, ChIP-seq, and scATAC-seq data indicates that YY1 controls numerous chromatin-modifying proteins leading to increased accessibility of alternative lineage genes in YY1 knockout pro-B cells. Given the ubiquitous nature of YY1 and its dual activation and repression functions, YY1 may regulate commitment in multiple cell lineages.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The area postrema: a critical mediator of brain-body interactions. 脑后区：脑-体互动的关键中介。

IF 7.5 1区生物学

Genes & development Pub Date : 2024-10-16 DOI: 10.1101/gad.352276.124

Daniëlle van de Lisdonk, Bo Li

引用次数: 0