FocusAAAS WACHTEL PRIZE ESSAY

Charting the “unknown unknowns” of cancer progression

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Science Translational Medicine  26 Jul 2017:
Vol. 9, Issue 400, eaao0959
DOI: 10.1126/scitranslmed.aao0959

Figures

  • Fig. 1. Discovery of regulatory pathways that drive cancer metastasis.

    (A) In highly metastatic cells, TARBP2 is transcriptionally up-regulated. This increased expression, in turn, leads to a higher rate of degradation and lower expression for its target transcripts. Because key suppressors of metastatic progression, such as ZNF395 and APP, are among TARBP2 targets, hyperactivation of this posttranscriptional pathway results in higher metastatic colonization of the lung by breast cancer cells. (B) The abundance of specific tRNAs is dysregulated in metastatic breast cancers. Changes in tRNA expression in turn affect the translation and degradation rates of mRNAs based on their codon content. Cancer cells can hijack this pathway to modulate the expression of key promoters and suppressors of metastasis. (C) Under stress, specific tRNAs are fragmented to form tRFs, a class of small noncoding RNAs. A number of these fragments, which are generated in poorly metastatic breast cancer cells, compete with endogenous transcripts for binding to the protective RNA binding protein YBX1. As a result of this reduced YBX1 activity, a large number of its target transcripts are destabilized and degraded. Because the YBX1 regulon includes key promoters of metastatic progression, tRF induction acts as a suppressive mechanism, which is largely blunted in highly metastatic cells.

    CREDIT: A. KITTERMAN/SCIENCE TRANSLATIONAL MEDICINE

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