Author
Davide Ruggero
Other affiliations: Fox Chase Cancer Center, University of Bologna, University of California, Berkeley ...read more
Bio: Davide Ruggero is an academic researcher from University of California, San Francisco. The author has contributed to research in topics: Translation (biology) & EIF4E. The author has an hindex of 49, co-authored 111 publications receiving 17167 citations. Previous affiliations of Davide Ruggero include Fox Chase Cancer Center & University of Bologna.
Papers published on a yearly basis
Papers
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Icahn School of Medicine at Mount Sinai1, University of Michigan2, Pasteur Institute3, University of California, San Francisco4, European Bioinformatics Institute5, University of California, San Diego6, University of North Carolina at Chapel Hill7, Fred Hutchinson Cancer Research Center8, Gladstone Institutes9, Buck Institute for Research on Aging10
TL;DR: A human–SARS-CoV-2 protein interaction map highlights cellular processes that are hijacked by the virus and that can be targeted by existing drugs, including inhibitors of mRNA translation and predicted regulators of the sigma receptors.
Abstract: A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein–protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19. A human–SARS-CoV-2 protein interaction map highlights cellular processes that are hijacked by the virus and that can be targeted by existing drugs, including inhibitors of mRNA translation and predicted regulators of the sigma receptors.
3,319 citations
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TL;DR: A requirement for VEGFR1+ haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells is demonstrated.
Abstract: The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1(+) cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin alpha4beta1), and that tumour-specific growth factors upregulate fibronectin--a VLA-4 ligand--in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread.
2,923 citations
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TL;DR: A clinically relevant ATP site inhibitor of mTOR, INK128, is developed, which reprograms this gene expression signature with therapeutic benefit for prostate cancer metastasis, for which there is presently no cure.
Abstract: The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth and cancer. However, the downstream translationally regulated nodes of gene expression that may direct cancer development are poorly characterized. Using ribosome profiling, we uncover specialized translation of the prostate cancer genome by oncogenic mTOR signalling, revealing a remarkably specific repertoire of genes involved in cell proliferation, metabolism and invasion. We extend these findings by functionally characterizing a class of translationally controlled pro-invasion messenger RNAs that we show direct prostate cancer invasion and metastasis downstream of oncogenic mTOR signalling. Furthermore, we develop a clinically relevant ATP site inhibitor of mTOR, INK128, which reprograms this gene expression signature with therapeutic benefit for prostate cancer metastasis, for which there is presently no cure. Together, these findings extend our understanding of how the 'cancerous' translation machinery steers specific cancer cell behaviours, including metastasis, and may be therapeutically targeted.
1,151 citations
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TL;DR: This work uses two novel and specific mTOR kinase domain inhibitors (PP242 and PP30) to show that pharmacological inhibition of mTOR blocks the phosphorylation of Akt at S473 and prevents its full activation, and shows that the TORKinib PP242 is a more effective mTORC1 inhibitor than rapamycin.
Abstract: The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals These signaling functions are distributed between at least two distinct mTOR protein complexes: mTORC1 and mTORC2 mTORC1 is sensitive to the selective inhibitor rapamycin and activated by growth factor stimulation via the canonical phosphoinositide 3-kinase (PI3K)-->Akt-->mTOR pathway Activated mTORC1 kinase up-regulates protein synthesis by phosphorylating key regulators of mRNA translation By contrast, mTORC2 is resistant to rapamycin Genetic studies have suggested that mTORC2 may phosphorylate Akt at S473, one of two phosphorylation sites required for Akt activation; this has been controversial, in part because RNA interference and gene knockouts produce distinct Akt phospho-isoforms The central role of mTOR in controlling key cellular growth and survival pathways has sparked interest in discovering mTOR inhibitors that bind to the ATP site and therefore target both mTORC2 and mTORC1 We investigated mTOR signaling in cells and animals with two novel and specific mTOR kinase domain inhibitors (TORKinibs) Unlike rapamycin, these TORKinibs (PP242 and PP30) inhibit mTORC2, and we use them to show that pharmacological inhibition of mTOR blocks the phosphorylation of Akt at S473 and prevents its full activation Furthermore, we show that TORKinibs inhibit proliferation of primary cells more completely than rapamycin Surprisingly, we find that mTORC2 is not the basis for this enhanced activity, and we show that the TORKinib PP242 is a more effective mTORC1 inhibitor than rapamycin Importantly, at the molecular level, PP242 inhibits cap-dependent translation under conditions in which rapamycin has no effect Our findings identify new functional features of mTORC1 that are resistant to rapamycin but are effectively targeted by TORKinibs These potent new pharmacological agents complement rapamycin in the study of mTOR and its role in normal physiology and human disease
1,129 citations
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TL;DR: Although many studies have correlated deregulation of protein biosynthesis with cancer, it remains to be established whether this translates directly into an increase in cancer susceptibility, and under what circumstances.
Abstract: Ribosome biogenesis and translation control are essential cellular processes that are governed at numerous levels. Several tumour suppressors and proto-oncogenes have been found either to affect the formation of the mature ribosome or to regulate the activity of proteins known as translation factors. Disruption in one or more of the steps that control protein biosynthesis has been associated with alterations in the cell cycle and regulation of cell growth. Therefore, certain tumour suppressors and proto-oncogenes might regulate malignant progression by altering the protein synthesis machinery. Although many studies have correlated deregulation of protein biosynthesis with cancer, it remains to be established whether this translates directly into an increase in cancer susceptibility, and under what circumstances.
910 citations
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TL;DR: The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.
Abstract: The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.
9,282 citations
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TL;DR: The principal mechanisms that govern the effects of inflammation and immunity on tumor development are outlined and attractive new targets for cancer therapy and prevention are discussed.
8,664 citations
01 Apr 2012
TL;DR: The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis as mentioned in this paper, and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration.
Abstract: The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation.
6,268 citations
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TL;DR: Recent advances in understanding of the mTOR pathway are reviewed and pharmacological approaches to treat human pathologies linked to mTOR deregulation are discussed.
5,792 citations
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TL;DR: The physiological consequences of mammalianTORC1 dysregulation suggest that inhibitors of mammalian TOR may be useful in the treatment of cancer, cardiovascular disease, autoimmunity, and metabolic disorders.
5,553 citations