1,720,997 research outputs found
Abstract 5561: Single-cell analysis reveals an adaptive, transiently heritable, slowly-dividing, drug-resistant state inhibitable by drug combinations
No full textAbstract
Adaptation and fractional response of tumor cells to targeted inhibitors of oncogenic pathways creates a population of viable tumor cells from which fully resistant clones can ultimately arise. Thus, understanding transient drug adaptation is key for both improving the effectiveness of treatment and delaying/controlling acquired resistance. Despite the wealth of information available about feedback mechanisms associated with adaptive resistance, most of our knowledge in this area comes from studying drug response in bulk tumor cell populations. Furthermore, the phenotypic consequences of drug adaptation have been often studied at a few fixed time-points, when drug-adapted cells exhibit a high population-average activity in multiple pro-growth signaling cascades. It therefore remains unclear how the initial responses to drug relate to subsequent phenotypes such as cell death or adaptation. This is likely a key point for designing novel approaches to overcome fractional drug response in tumor cells and to achieve durable therapy.
We use real-time live-cell imaging, single-cell analysis and molecular profiling to show that exposure of BRAFV600E melanoma cells to RAF/MEK inhibitors elicits a time-variable and heterogeneous response in which some cells die, some arrest and the remainder adapt to drug. Drug-adapted cells up-regulate markers of the neural crest (e.g. NGFR), a melanocyte precursor, and grow slowly. The drug-induced slowly-cycling NFGRHigh state is only transiently stable, reverting to the drug-naïve state within two weeks of drug withdrawal as measured by the restoration of RAF/MEK inhibitor sensitivity, accelerated rate of cell division and reduced expression of NGFR. Transcriptional and biochemical profiling of cell lines and human tumors implicates a role for the c-Jun/ECM/FAK/Src cascade in driving the de-differentiated resistance program. We identify multiple drugs targeting this cascade as well as BET bromodomain inhibitors that block this resistance program in cell lines and in a BRAFV600E melanoma xenograft model and increase sensitivity and maximal effect (Emax) of RAF/MEK inhibitors. Our study reveals directly how drug adaptation happens in individual tumor cells leading to emergence of heterogeneous cell sub-populations with reduced drug-sensitivity that may be targeted by drug combinations.
Citation Format: Mohammad Fallahi-Sichani, Verena Becker, Benjamin Izar, Gregory J. Baker, Jia-Ren Lin, Sarah A. Boswell, Levi A. Garraway, Peter K. Sorger. Single-cell analysis reveals an adaptive, transiently heritable, slowly-dividing, drug-resistant state inhibitable by drug combinations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5561. doi:10.1158/1538-7445.AM2017-5561</jats:p
Abstract PR17: Single-cell analysis reveals an adaptive, slowly-dividing, de-differentiated, drug-resistant cell state selectively inhibitable by drug combinations
No full textAbstract
Partial responsiveness of tumor cells due to drug adaptation (or tolerance) during the early phase of treatment with targeted therapeutics seems to be essential for creating a population of viable tumor cells from which resistant clones eventually arise. Thus, understanding transient drug adaptation is likely to be important for both improving the initial effectiveness of treatment and delaying or controlling acquired resistance. Despite the wealth of information available about the molecular events and feedback mechanisms leading to drug tolerance or adaptation, most of our knowledge in this area comes from studying drug response in bulk tumor cell populations. Furthermore, the phenotypic consequences of drug adaptation have been studied most frequently at a few fixed time-points, when drug-adapted cells exhibit a high population-average activity in multiple pro-growth or pro-survival signaling cascades. Therefore, it remains unclear how uniform or heterogeneous the early drug adaptation is across individual cells within a tumor cell population, and how the fate of drug-adapted cells is determined by a diversity of early drug-induced adaptive signaling responses. Uncovering the evolution of biochemical and phenotypic heterogeneity in drug-adapted cell populations is key to designing optimal combinations of drugs to overcome resistance and to achieve durable therapy.
In this study, we monitor the responses of BRAFV600E melanoma cells to RAF/MEK inhibitors at the single-cell level in real time using time-lapse live-cell imaging, and then analyze the resulting cell states using transcriptional, biochemical and phenotypic profiling. We found that exposure of tumor cells to RAF/MEK inhibitors elicits heterogeneous and time-variable responses in which some cells die, some arrest and a fraction of slowly-cycling cells adapts to drug, adopting a reversible drug-resistance phenotype characterized by up-regulation of markers of neural crest, a melanocyte precursor, including NGFR (the low affinity nerve growth factor receptor, also known as p75NTR or CD271). The slowly-cycling NFGRHigh state induced by RAF/MEK inhibitors is only transiently stable: after 1-2 weeks of outgrowth in drug-free medium, such cells reset to their initial state as measured by the restoration of RAF/MEK inhibitor sensitivity, accelerated rate of cell division and reduced expression of NGFR. Transcriptional and biochemical profiling of cell lines and human tumors implicates a role for the c-Jun/ECM/FAK/Src cascade in driving the de-differentiated (NGFRHigh) resistance program. We identify multiple drugs targeting this cascade as well as BET bromodomain inhibitors that block the slowly-cycling NGFRHigh state in cell lines and in a BRAFV600E melanoma xenograft model and increase sensitivity to RAF/MEK inhibitors. Our study reveals directly how drug adaptation happens in individual tumor cells leading to emergence of heterogeneous cell sub-populations with reduced drug-sensitivity that may be selectively targeted by drug combinations.
Citation Format: Mohammad Fallahi-Sichani, Verena Becker, Benjamin Izar, Gregory J. Baker, Jia-Ren Lin, Sarah A. Boswell, Levi A. Garraway, Peter K. Sorger. Single-cell analysis reveals an adaptive, slowly-dividing, de-differentiated, drug-resistant cell state selectively inhibitable by drug combinations [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr PR17.</jats:p
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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