Cold Spring Harbor symposia on quantitative biology最新文献_第10页

Targeting the Epithelial-to-Mesenchymal Transition: The Case for Differentiation-Based Therapy 靶向上皮细胞到间质细胞的转变:基于分化治疗的案例

Cold Spring Harbor symposia on quantitative biology Pub Date : 2017-01-05 DOI: 10.1101/sqb.2016.81.030957

D. Pattabiraman, R. Weinberg

{"title":"Targeting the Epithelial-to-Mesenchymal Transition: The Case for Differentiation-Based Therapy","authors":"D. Pattabiraman, R. Weinberg","doi":"10.1101/sqb.2016.81.030957","DOIUrl":"https://doi.org/10.1101/sqb.2016.81.030957","url":null,"abstract":"Although important strides have been made in targeted therapy for certain leukemias and subtypes of breast cancer, the standard of care for most carcinomas still involves chemotherapy, radiotherapy, surgery, or a combination of these. Two processes serve as obstacles to the successful treatment of carcinomas. First, a majority of deaths from these types of cancers occurs as a result of distant metastases and not the primary tumors themselves. Second, subsets of cells that are able to survive conventional therapy drive the aggressive relapse of the tumors, often in forms that are resistant to treatment. A frequently observed feature of malignant carcinomas is the loss of epithelial traits and the gain of certain mesenchymal ones that are programmed by the cell-biological program termed the epithelial-to-mesenchymal transition (EMT). The EMT program can confer (i) an ability to disseminate, (ii) an ability to become stem-like tumor-initiating cells, (iii) an ability to found new tumor colonies at distant anatomical sites, and (iv) an elevated resistance to therapy. These multiple powers of the EMT program explain why it has become an attractive target for therapeutic intervention. Recent work has revealed the variable nature of the EMT, with multiple versions of the program being observed depending on the tissue context and the stage of tumor progression. In this review, we attempt to crystallize emerging concepts in the research on EMT and stemness and discuss the benefits of using a differentiation-based therapeutic strategy for the eradication of stem-like populations that have adopted various versions of the EMT program.","PeriodicalId":72635,"journal":{"name":"Cold Spring Harbor symposia on quantitative biology","volume":"1161 1","pages":"11 - 19"},"PeriodicalIF":0.0,"publicationDate":"2017-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72690018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 53

A Pipeline for Drug Target Identification and Validation 药物靶点鉴定和验证的管道

Cold Spring Harbor symposia on quantitative biology Pub Date : 2017-01-05 DOI: 10.1101/sqb.2016.81.031096

Eusebio Manchado, Chun-Hao Huang, Nilgun Tasdemir, Darjus F. Tschaharganeh, J. Wilkinson, S. Lowe

{"title":"A Pipeline for Drug Target Identification and Validation","authors":"Eusebio Manchado, Chun-Hao Huang, Nilgun Tasdemir, Darjus F. Tschaharganeh, J. Wilkinson, S. Lowe","doi":"10.1101/sqb.2016.81.031096","DOIUrl":"https://doi.org/10.1101/sqb.2016.81.031096","url":null,"abstract":"Rapid and affordable tumor profiling has led to an explosion of genomic data that is facilitating the development of new cancer therapies. The potential of therapeutic strategies aimed at inactivating the oncogenic lesions that contribute to the aberrant survival and proliferation of tumor cells has yielded remarkable success in some malignancies such as BRAF-mutant melanoma and BCR-ABL expressing chronic myeloid leukemia. However, the direct inhibition of several well-established oncoproteins in some of these cancers is not possible or produces only transient benefits. Functional genomics represents a powerful approach for the identification of vulnerabilities linked to specific genetic alterations and has provided substantial insights into cancer signaling networks. Still, as inhibition of gene function can have diverse effects on both tumor and normal tissues, information on the potency of target inhibition on tumor growth as well as the toxic side effects of target inhibition are also needed. Here, we discuss our RNA interference (RNAi) pipeline for cancer target discovery based on our optimized short-hairpin RNA (shRNA) tools for negative selection screens and inducible RNAi platform that, in combination with embryonic stem cell (ESC)-based genetically engineered mouse models (GEMMs), enable deep in vivo target validation.","PeriodicalId":72635,"journal":{"name":"Cold Spring Harbor symposia on quantitative biology","volume":"20 1","pages":"257 - 267"},"PeriodicalIF":0.0,"publicationDate":"2017-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81860567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 13

Shaping Chromatin in the Nucleus: The Bricks and the Architects. 在细胞核中形成染色质:砖块和建筑师。

Cold Spring Harbor symposia on quantitative biology Pub Date : 2017-01-01 Epub Date: 2017-12-05 DOI: 10.1101/sqb.2017.82.033753

David Sitbon, Katrina Podsypanina, Tejas Yadav, Geneviève Almouzni

{"title":"Shaping Chromatin in the Nucleus: The Bricks and the Architects.","authors":"David Sitbon, Katrina Podsypanina, Tejas Yadav, Geneviève Almouzni","doi":"10.1101/sqb.2017.82.033753","DOIUrl":"https://doi.org/10.1101/sqb.2017.82.033753","url":null,"abstract":"Chromatin organization in the nucleus provides a vast repertoire of information in addition to that encoded genetically. Understanding how this organization impacts genome stability and influences cell fate and tumorigenesis is an area of rapid progress. Considering the nucleosome, the fundamental unit of chromatin structure, the study of histone variants (the bricks) and their selective loading by histone chaperones (the architects) is particularly informative. Here, we report recent advances in understanding how relationships between histone variants and their chaperones contribute to tumorigenesis using cell lines and Xenopus development as model systems. In addition to their role in histone deposition, we also document interactions between histone chaperones and other chromatin factors that govern higher-order structure and control DNA metabolism. We highlight how a fine-tuned assembly line of bricks (H3.3 and CENP-A) and architects (HIRA, HJURP, and DAXX) is key in adaptation to developmental and pathological changes. An example of this conceptual advance is the exquisite sensitivity displayed by p53-null tumor cells to modulation of HJURP, the histone chaperone for CENP-A (CenH3 variant). We discuss how these findings open avenues for novel therapeutic paradigms in cancer care.","PeriodicalId":72635,"journal":{"name":"Cold Spring Harbor symposia on quantitative biology","volume":"82 ","pages":"1-14"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1101/sqb.2017.82.033753","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35618823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 21

Genome Instability as a Consequence of Defects in the Resolution of Recombination Intermediates. 基因组不稳定性是重组中间体分解缺陷的后果

Cold Spring Harbor symposia on quantitative biology Pub Date : 2017-01-01 Epub Date: 2018-01-18 DOI: 10.1101/sqb.2017.82.034256

Stephen C West, Ying Wai Chan

{"title":"Genome Instability as a Consequence of Defects in the Resolution of Recombination Intermediates.","authors":"Stephen C West, Ying Wai Chan","doi":"10.1101/sqb.2017.82.034256","DOIUrl":"10.1101/sqb.2017.82.034256","url":null,"abstract":"The efficient processing of homologous recombination (HR) intermediates, which often contain four-way structures known as Holliday junctions (HJs), is required for proper chromosome segregation at mitosis. Eukaryotic cells possess three distinct pathways of resolution: (i) HJ dissolution mediated by BLM-topoisomerase IIIα-RMI1-RMI2 (BTR) complex, and HJ resolution catalyzed by either (ii) SLX1-SLX4-MUS81-EME1-XPF-ERCC1 (SMX complex) or (iii) GEN1. The BTR pathway acts at all times throughout the cell cycle, whereas the actions of SMX and GEN1 are restrained in S phase and become elevated late in the cell cycle to ensure the resolution of persistent recombination intermediates before mitotic division. By developing a \"resolvase-deficient\" model system in which the activities of MUS81 and GEN1 are compromised, we have explored the fate of unresolved recombination intermediates. We find that covalently linked sister chromatids promote the formation of a new class of ultrafine bridges at anaphase that we term HR-UFBs. These bridges are broken at cell division, leading to activation of the DNA damage checkpoint and repair by nonhomologous end joining (NHEJ) in the next cell cycle. As a consequence, high levels of gross chromosomal rearrangements and aberrations are observed, together with frequent cell death. These results show that the HJ resolvases provide essential functions for the resolution of recombination intermediates, even in cells that remain proficient for BTR-mediated HJ dissolution.","PeriodicalId":72635,"journal":{"name":"Cold Spring Harbor symposia on quantitative biology","volume":"82 ","pages":"207-212"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35748511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Symmetry from Asymmetry or Asymmetry from Symmetry? 对称源自不对称还是对称源自对称?

Cold Spring Harbor symposia on quantitative biology Pub Date : 2017-01-01 Epub Date: 2018-01-18 DOI: 10.1101/sqb.2017.82.034272

Elizabeth W Kahney, Rajesh Ranjan, Ryan J Gleason, Xin Chen

{"title":"Symmetry from Asymmetry or Asymmetry from Symmetry?","authors":"Elizabeth W Kahney, Rajesh Ranjan, Ryan J Gleason, Xin Chen","doi":"10.1101/sqb.2017.82.034272","DOIUrl":"https://doi.org/10.1101/sqb.2017.82.034272","url":null,"abstract":"The processes of DNA replication and mitosis allow the genetic information of a cell to be copied and transferred reliably to its daughter cells. However, if DNA replication and cell division were always performed in a symmetric manner, the result would be a cluster of tumor cells instead of a multicellular organism. Therefore, gaining a complete understanding of any complex living organism depends on learning how cells become different while faithfully maintaining the same genetic material. It is well recognized that the distinct epigenetic information contained in each cell type defines its unique gene expression program. Nevertheless, how epigenetic information contained in the parental cell is either maintained or changed in the daughter cells remains largely unknown. During the asymmetric cell division (ACD) of Drosophila male germline stem cells, our previous work revealed that preexisting histones are selectively retained in the renewed stem cell daughter, whereas newly synthesized histones are enriched in the differentiating daughter cell. We also found that randomized inheritance of preexisting histones versus newly synthesized histones results in both stem cell loss and progenitor germ cell tumor phenotypes, suggesting that programmed histone inheritance is a key epigenetic player for cells to either remember or reset cell fates. Here, we will discuss these findings in the context of current knowledge on DNA replication, polarized mitotic machinery, and ACD for both animal development and tissue homeostasis. We will also speculate on some potential mechanisms underlying asymmetric histone inheritance, which may be used in other biological events to achieve the asymmetric cell fates.","PeriodicalId":72635,"journal":{"name":"Cold Spring Harbor symposia on quantitative biology","volume":"82 ","pages":"305-318"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1101/sqb.2017.82.034272","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35748512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 20

A Conversation with Bernard de Massy. 《与伯纳德·德·马西的对话》

Cold Spring Harbor symposia on quantitative biology Pub Date : 2017-01-01 Epub Date: 2018-04-02 DOI: 10.1101/sqb.2017.82.034538

引用次数: 0

A Conversation with Kerry Bloom. 《与克里·布鲁姆的对话》

Cold Spring Harbor symposia on quantitative biology Pub Date : 2017-01-01 Epub Date: 2018-03-26 DOI: 10.1101/sqb.2017.82.034488

{"title":"A Conversation with Kerry Bloom.","authors":"","doi":"10.1101/sqb.2017.82.034488","DOIUrl":"https://doi.org/10.1101/sqb.2017.82.034488","url":null,"abstract":"Dr. Bloom: The chromosome, in the public domain right now, is “the sequence.” Of course, there’s much more in the chromosome than the DNA sequence. That’s going to be the challenge for us moving forward: How do you store information? How do you propagate information beyond just the sequence of nucleic acids? Scientists have watched chromosomes move for hundreds of years, and it’s a ballet. They do this beautiful movement back and forth, literally dancing around each other until they finally all line up—I use that word loosely —and then go to what will be daughter cells. The accuracy that they must achieve to segregate all 46 chromosomes roughly 10 trillion times for all the cells in our body is beyond anything that’s ever been man-made. To get to your explicit question, they achieve that accuracy by building a spring between the twomicrotubule attachment sites. However, they don’t count chromosomes. You could have imagined a mechanism where they’re counting: “Is 1 lined up? Is 2 lined up?... Is 45 lined up? When 46 is lined up, let’s go.” They don’t do that. They build a little spring between the two microtubules from opposite spindle poles, and when that spring is under some tension, it quenches a checkpoint that is responsible for delaying the next phase of the cell cycle, when chromosomes segregate. If even one chromosome is still left behind (i.e., the spring is not under tension), that’ll suffice to delay the cell cycle. We’re interested in how that chromosome spring works. That region of the chromosome is called the centromere. There’s 6 feet of DNA in one cell. How do you take this very floppy molecule and build a molecular spring? That, basically, was our challenge.","PeriodicalId":72635,"journal":{"name":"Cold Spring Harbor symposia on quantitative biology","volume":"82 ","pages":"375-377"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1101/sqb.2017.82.034488","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35949379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Conversation with Marisa Bartolomei. 与玛丽莎·巴托洛梅的对话。

Cold Spring Harbor symposia on quantitative biology Pub Date : 2017-01-01 Epub Date: 2018-03-27 DOI: 10.1101/sqb.2017.82.034447

引用次数: 0

Aurora A Kinase Function at Kinetochores. 着丝点上Aurora A激酶的功能。

Cold Spring Harbor symposia on quantitative biology Pub Date : 2017-01-01 Epub Date: 2018-04-26 DOI: 10.1101/sqb.2017.82.034991

Jennifer G DeLuca

引用次数: 7

RotoStep: A Chromosome Dynamics Simulator Reveals Mechanisms of Loop Extrusion. RotoStep:染色体动力学模拟器揭示了环挤压机制。

Cold Spring Harbor symposia on quantitative biology Pub Date : 2017-01-01 Epub Date: 2017-11-22 DOI: 10.1101/sqb.2017.82.033696

Josh Lawrimore, Brandon Friedman, Ayush Doshi, Kerry Bloom

引用次数: 21