Showing papers by "Angelika Amon published in 2017"
TL;DR: In this article, the authors investigated the immediate consequences of aneuploidy on cell physiology and identified mechanisms that eliminate anauploid cells by finding that chromosome mis-segregation leads to further genomic instability that ultimately causes cell-cycle arrest.
239 citations
TL;DR: It is found that nearly all trisomic cell lines grew poorly in vitro and as xenografts, relative to genetically matched euploid cells, and the activation of several oncogenic pathways failed to alleviate the fitness defect induced by aneuploidy.
159 citations
TL;DR: It is proposed that non-genetic individuality is a universal characteristic of the aneuploid state that may contribute to variability in presentation and treatment responses of diseases caused by aneuPLoidy.
78 citations
06 Mar 2017
TL;DR: Using large-scale tumor sequencing efforts to assess karyotypic alterations across many cancer types and review recent sequencing studies that show how karyotypes change in space and time, findings are summarized.
Abstract: Aneuploidy, the state of having gained or lost chromosomes, is a hallmark of cancer. Approximately 90% of tumors have gained or lost at least one chromosome. In spite of aneuploidy occurring as frequently as, if not more often than, disruption of the p53 pathway, whether and how aneuploidy influences tumorigenesis is still poorly understood. Here, we take advantage of large-scale tumor sequencing efforts to assess karyotypic alterations across many cancer types and review recent sequencing studies that show how karyotypes change in space and time. We further summarize findings that describe the effects of aneuploidy on untransformed cells, the mechanisms by which aneuploidy could drive tumorigenesis, and the potential to target aneuploidy for cancer therapy.
55 citations
TL;DR: The results offer pharmacologic evidence that the aneuploid state in cancer cells can be targeted selectively for therapeutic purposes, or for reducing the toxicity of taxane-based drug regimens.
Abstract: Aneuploidy, a hallmark of cancer cells, poses an appealing opportunity for cancer treatment and prevention strategies. Using a cell-based screen to identify small molecules that could selectively kill aneuploid cells, we identified the compound N-[2-hydroxy-1-(4-morpholinylmethyl)-2-phenylethyl]-decanamide monohydrochloride (DL-PDMP), an antagonist of UDP-glucose ceramide glucosyltransferase. DL-PDMP selectively inhibited proliferation of aneuploid primary mouse embryonic fibroblasts and aneuploid colorectal cancer cells. Its selective cytotoxic effects were based on further accentuating the elevated levels of ceramide, which characterize aneuploid cells, leading to increased apoptosis. We observed that DL-PDMP could also enhance the cytotoxic effects of paclitaxel, a standard-of-care chemotherapeutic agent that causes aneuploidy, in human colon cancer and mouse lymphoma cells. Our results offer pharmacologic evidence that the aneuploid state in cancer cells can be targeted selectively for therapeutic purposes, or for reducing the toxicity of taxane-based drug regimens. Cancer Res; 77(19); 5272-86. ©2017 AACR.
32 citations
01 Jan 2017
TL;DR: In this article, a cell-based screen was used to identify small molecules that could selectively kill aneuploid cells, and they identified the compound N-[2-hydroxy-1-(4-morpholinylmethyl)-2-phenylethyl]-decanamide monohydrochloride (DL-PDMP), an antagonist of UDP-glucose ceramide glucosyltransferase.
Abstract: Aneuploidy, a hallmark of cancer cells, poses an appealing opportunity for cancer treatment and prevention strategies. Using a cell-based screen to identify small molecules that could selectively kill aneuploid cells, we identified the compound N-[2-hydroxy-1-(4-morpholinylmethyl)-2-phenylethyl]-decanamide monohydrochloride (DL-PDMP), an antagonist of UDP-glucose ceramide glucosyltransferase. DL-PDMP selectively inhibited proliferation of aneuploid primary mouse embryonic fibroblasts and aneuploid colorectal cancer cells. Its selective cytotoxic effects were based on further accentuating the elevated levels of ceramide, which characterize aneuploid cells, leading to increased apoptosis. We observed that DL-PDMP could also enhance the cytotoxic effects of paclitaxel, a standard-of-care chemotherapeutic agent that causes aneuploidy, in human colon cancer and mouse lymphoma cells. Our results offer pharmacologic evidence that the aneuploid state in cancer cells can be targeted selectively for therapeutic purposes, or for reducing the toxicity of taxane-based drug regimens. Cancer Res; 77(19); 5272-86. ©2017 AACR.
20 citations
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Johns Hopkins University1, Massachusetts Institute of Technology2, Yale University3, Howard Hughes Medical Institute4, Stanford University5, University of Utah6, Princeton University7, University of California, Berkeley8, California Institute of Technology9, Harvard University10, University of Colorado Boulder11, University of Maryland, College Park12, Johns Hopkins University School of Medicine13, Rockefeller University14, University of Wisconsin-Madison15, University of Washington16, New York University17, Brandeis University18, University of California, San Francisco19, University of Texas Southwestern Medical Center20, Carnegie Institution for Science21, University of Michigan22
TL;DR: In her Science Insider News Story “Salk Institute hit with discrimination lawsuit by third female scientist” (20 July, ) M. Wadman reports that three of the four senior women scientists at the Salk Institute have filed a lawsuit alleging gender discrimination.
Abstract: In her Science Insider News Story “Salk Institute hit with discrimination lawsuit by third female scientist” (20 July, ) M. Wadman reports that three of the four senior women scientists at the Salk Institute have filed a lawsuit alleging gender discrimination. The
5 citations