Translational Regulation of Cancer Metastasis

Deregulation of the mRNA translational process has been observed during tumorigenesis. However, recent findings have shown that deregulation of translation also contributes specifically to cancer cell spread. During metastasis, cancer cells undergo changes in cellular state, permitting the acquisition of features necessary for cell survival, dissemination, and outgrowth. In addition, metastatic cells respond to external cues, allowing for their persistence under significant cellular and microenvironmental stresses. Recent work has revealed the importance of mRNA translation to these dynamic changes, including regulation of cell states through epithelial-to-mesenchymal transition and tumor dormancy and as a response to external stresses such as hypoxia and immune surveillance. In this review, we focus on examples of altered translation underlying these phenotypic changes and responses to external cues and explore how they contribute to metastatic progression. We also highlight the therapeutic opportunities presented by aberrant mRNA translation, suggesting novel ways to target metastatic tumor cells.

[1]  H. Munshi,et al.  Controlling TIME: How MNK Kinases Function to Shape Tumor Immunity , 2020, Cancers.

[2]  P. A. Thompson,et al.  Design of Development Candidate eFT226, a First in Class Inhibitor of Eukaryotic Initiation Factor 4A RNA Helicase. , 2020, Journal of medicinal chemistry.

[3]  Gaspar P. Pinto,et al.  Transcription and Translation Inhibitors in Cancer Treatment , 2020, Frontiers in Chemistry.

[4]  Kathryn A. O’Donnell,et al.  eIF5B drives integrated stress response-dependent translation of PD-L1 in lung cancer , 2020, Nature Cancer.

[5]  P. Andrade,et al.  Endoplasmic reticulum stress signaling in cancer and neurodegenerative disorders: tools and strategies to understand its complexity. , 2020, Pharmacological research.

[6]  Ben S. Wittner,et al.  Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis , 2020, Science.

[7]  Manuel A. S. Santos,et al.  tRNA Deregulation and Its Consequences in Cancer. , 2019, Trends in molecular medicine.

[8]  H. Hua,et al.  Targeting mTOR for cancer therapy , 2019, Journal of Hematology & Oncology.

[9]  Yun Wang,et al.  Eukaryotic initiation factor 4A2 promotes experimental metastasis and oxaliplatin resistance in colorectal cancer , 2019, Journal of Experimental & Clinical Cancer Research.

[10]  I. Dutta,et al.  Translational control of breast cancer plasticity , 2019, bioRxiv.

[11]  N. Ferrara,et al.  VEGF in Signaling and Disease: Beyond Discovery and Development , 2019, Cell.

[12]  K. Shokat,et al.  Chronic TGF-β exposure drives stabilized EMT, tumor stemness, and cancer drug resistance with vulnerability to bitopic mTOR inhibition , 2019, Science Signaling.

[13]  Yuquan Wei,et al.  Targeting PI3K in cancer: mechanisms and advances in clinical trials , 2019, Molecular Cancer.

[14]  N. Beerenwinkel,et al.  Neutrophils escort circulating tumour cells to enable cell cycle progression , 2019, Nature.

[15]  Y. Wang,et al.  Translation control of the immune checkpoint in cancer and its therapeutic targeting , 2019, Nature Medicine.

[16]  N. Sonenberg,et al.  Translational control of tumor immune escape via the eIF4F–STAT1–PD-L1 axis in melanoma , 2018, Nature Medicine.

[17]  N. Sonenberg,et al.  Translational Control in Cancer. , 2018, Cold Spring Harbor perspectives in biology.

[18]  P. A. Thompson,et al.  Structure-based Design of Pyridone-Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibition. , 2018, Journal of medicinal chemistry.

[19]  E. Ma,et al.  Translational control in the tumor microenvironment promotes lung metastasis: Phosphorylation of eIF4E in neutrophils , 2018, Proceedings of the National Academy of Sciences.

[20]  P. V. van Diest,et al.  Targeting RNA helicases in cancer: The translation trap. , 2017, Biochimica et biophysica acta. Reviews on cancer.

[21]  J. Uniacke,et al.  The eIF4E2-Directed Hypoxic Cap-Dependent Translation Machinery Reveals Novel Therapeutic Potential for Cancer Treatment , 2017, Oxidative medicine and cellular longevity.

[22]  D. Beer,et al.  Poor Prognosis Indicated by Venous Circulating Tumor Cell Clusters in Early-Stage Lung Cancers. , 2017, Cancer research.

[23]  K. Fujii,et al.  Heterogeneous Ribosomes Preferentially Translate Distinct Subpools of mRNAs Genome-wide. , 2017, Molecular cell.

[24]  J. Bradner,et al.  Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma , 2017, Science Translational Medicine.

[25]  N. Sonenberg,et al.  Translational control and the cancer cell response to stress. , 2017, Current opinion in cell biology.

[26]  G. Pavitt,et al.  Fail-safe control of translation initiation by dissociation of eIF2α phosphorylated ternary complexes , 2017, eLife.

[27]  C. Shaw,et al.  CELF1 is a central node in post-transcriptional regulatory programmes underlying EMT , 2016, Nature Communications.

[28]  C. Robert,et al.  Molecular Pathways: The eIF4F Translation Initiation Complex—New Opportunities for Cancer Treatment , 2016, Clinical Cancer Research.

[29]  Mila Ljujic,et al.  The integrated stress response , 2016, EMBO reports.

[30]  S. Marzi,et al.  Nucleolin Promotes Heat Shock-Associated Translation of VEGF-D to Promote Tumor Lymphangiogenesis. , 2016, Cancer research.

[31]  M. Berger,et al.  Abstract 2147: Overcoming mTOR resistance mutations with a new generation mTOR inhibitor , 2016 .

[32]  P. Bendahl,et al.  Prognostic impact of circulating tumor cell apoptosis and clusters in serial blood samples from patients with metastatic breast cancer in a prospective observational cohort , 2016, BMC Cancer.

[33]  R. Wek,et al.  Upstream Open Reading Frames Differentially Regulate Gene-specific Translation in the Integrated Stress Response* , 2016, The Journal of Biological Chemistry.

[34]  A. Hinnebusch,et al.  Translational control by 5′-untranslated regions of eukaryotic mRNAs , 2016, Science.

[35]  K. E. Visser,et al.  Neutrophils in cancer: neutral no more , 2016, Nature Reviews Cancer.

[36]  Beth Walters,et al.  Cap-Independent Translational Control of Carcinogenesis , 2016, Front. Oncol..

[37]  P. Brousset,et al.  PERK mediates the IRES-dependent translational activation of mRNAs encoding angiogenic growth factors after ischemic stress , 2016, Science Signaling.

[38]  Chuanhao Tang,et al.  Over-expressed RPL34 promotes malignant proliferation of non-small cell lung cancer cells. , 2016, Gene.

[39]  Oded Meyuhas,et al.  The race to decipher the top secrets of TOP mRNAs. , 2015, Biochimica et biophysica acta.

[40]  N. Sonenberg,et al.  Targeting the eIF4F translation initiation complex: a critical nexus for cancer development. , 2015, Cancer research.

[41]  Sridhar Ramaswamy,et al.  Circulating Tumor Cell Clusters Are Oligoclonal Precursors of Breast Cancer Metastasis , 2014, Cell.

[42]  P. Bragado,et al.  Mechanisms of disseminated cancer cell dormancy: an awakening field , 2014, Nature Reviews Cancer.

[43]  Michael Detmar,et al.  Mechanisms of lymphatic metastasis. , 2014, The Journal of clinical investigation.

[44]  P. Carmeliet,et al.  Hypoxia induces VEGF-C expression in metastatic tumor cells via a HIF-1α-independent translation-mediated mechanism. , 2014, Cell reports.

[45]  M. Lleonart,et al.  Ribosomal proteins as novel players in tumorigenesis , 2013, Cancer and Metastasis Reviews.

[46]  C. Dang MYC, metabolism, cell growth, and tumorigenesis. , 2013, Cold Spring Harbor perspectives in medicine.

[47]  R. Kaufman,et al.  ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death , 2013, Nature Cell Biology.

[48]  Sridhar Ramaswamy,et al.  Circulating Breast Tumor Cells Exhibit Dynamic Changes in Epithelial and Mesenchymal Composition , 2013, Science.

[49]  J. Somers,et al.  RNA Binding Protein/RNA Element Interactions and the Control of Translation , 2012, Current protein & peptide science.

[50]  James W. Smyth,et al.  TGF-β-induced activation of mTOR complex 2 drives epithelial–mesenchymal transition and cell invasion , 2012, Development.

[51]  A. Pause,et al.  An oxygen-regulated switch in the protein synthesis machinery , 2012, Nature.

[52]  Nicholas T. Ingolia,et al.  The translational landscape of mTOR signalling steers cancer initiation and metastasis , 2012, Nature.

[53]  Hongkai Ji,et al.  Cell-Type Independent MYC Target Genes Reveal a Primordial Signature Involved in Biomass Accumulation , 2011, PloS one.

[54]  Robert A. Weinberg,et al.  Tumor Metastasis: Molecular Insights and Evolving Paradigms , 2011, Cell.

[55]  J. Debnath,et al.  PERK Integrates Autophagy and Oxidative Stress Responses To Promote Survival during Extracellular Matrix Detachment , 2011, Molecular and Cellular Biology.

[56]  H. Weiss,et al.  mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. , 2011, Cancer research.

[57]  N. Sonenberg,et al.  Therapeutic inhibition of MAP kinase interacting kinase blocks eukaryotic initiation factor 4E phosphorylation and suppresses outgrowth of experimental lung metastases. , 2011, Cancer research.

[58]  P. Howe,et al.  Identification of an mRNP complex regulating tumorigenesis at the translational elongation step. , 2011, Molecular cell.

[59]  S. Willimott,et al.  Post-transcriptional and post-translational regulation of Bcl2. , 2010, Biochemical Society transactions.

[60]  R. Schneider Translational control of breast cancer , 2010 .

[61]  D. Ruggero The role of Myc-induced protein synthesis in cancer. , 2009, Cancer research.

[62]  R. Huang,et al.  Epithelial-Mesenchymal Transitions in Development and Disease , 2009, Cell.

[63]  M. Serrano,et al.  Rplp1 bypasses replicative senescence and contributes to transformation. , 2009, Experimental cell research.

[64]  Robbie Loewith,et al.  Active-Site Inhibitors of mTOR Target Rapamycin-Resistant Outputs of mTORC1 and mTORC2 , 2009, PLoS biology.

[65]  F. Lenfant,et al.  FGF2 Translationally Induced by Hypoxia Is Involved in Negative and Positive Feedback Loops with HIF-1α , 2008, PloS one.

[66]  K. Nakai,et al.  Comprehensive detection of human terminal oligo-pyrimidine (TOP) genes and analysis of their characteristics , 2008, Nucleic acids research.

[67]  R. Eils,et al.  Systemic spread is an early step in breast cancer. , 2008, Cancer cell.

[68]  A. Mercurio Faculty Opinions recommendation of Cell size and invasion in TGF-beta-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway. , 2007 .

[69]  W. Plunkett,et al.  A sequential blockade strategy for the design of combination therapies to overcome oncogene addiction in chronic myelogenous leukemia. , 2006, Cancer research.

[70]  J. Blenis,et al.  Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways , 2006, Oncogene.

[71]  C. Knabbe,et al.  TGF‐Beta Signaling in Breast Cancer , 2006, Annals of the New York Academy of Sciences.

[72]  R. Eils,et al.  Genomic analysis of single cytokeratin-positive cells from bone marrow reveals early mutational events in breast cancer. , 2005, Cancer cell.

[73]  Christopher G. Proud,et al.  A Novel mTOR-Regulated Phosphorylation Site in Elongation Factor 2 Kinase Modulates the Activity of the Kinase and Its Binding to Calmodulin , 2004, Molecular and Cellular Biology.

[74]  Dae‐Ghon Kim,et al.  Over‐expression of the ribosomal protein L36a gene is associated with cellular proliferation in hepatocellular carcinoma , 2004, Hepatology.

[75]  D. Ron,et al.  Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase , 1999, Nature.

[76]  P. Einat,et al.  Translation of Vascular Endothelial Growth Factor mRNA by Internal Ribosome Entry: Implications for Translation under Hypoxia , 1998, Molecular and Cellular Biology.

[77]  A. Palotie,et al.  Genomic Organization of Human and Mouse Genes for Vascular Endothelial Growth Factor C* , 1997, The Journal of Biological Chemistry.

[78]  R. Matkowski,et al.  Circulating Tumor , 2014 .

[79]  Meir Wetzler,et al.  Omacetaxine as an anticancer therapeutic: what is old is new again. , 2011, Current pharmaceutical design.

[80]  S. Huh,et al.  Tumor and Stem Cell Biology Cancer Research Transiently Entrapped Circulating Tumor Cells Interact with Neutrophils to Facilitate Lung Metastasis Development , 2010 .