Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease

Varsha Prakash; Brittany B. Carson; Jennifer M. Feenstra; Randall A. Dass; Petra Sekyrova; Ayuko Hoshino; Julian Petersen; Yuan Guo; Matthew M. Parks; Chad M. Kurylo; Jake E. Batchelder; Kristian Haller; Ayako Hashimoto; Helene Rundqivst; John S. Condeelis; C. David Allis; Denis Drygin; M. Angela Nieto; Michael Andäng; Piergiorgio Percipalle; Jonas Bergh; Igor Adameyko; Ann Kristin Östlund Farrants; Johan Hartman; David Lyden; Kristian Pietras; Scott C. Blanchard; C. Theresa Vincent

doi:10.1038/s41467-019-10100-8

Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease

Varsha Prakash, Brittany B. Carson, Jennifer M. Feenstra, Randall A. Dass, Petra Sekyrova, Ayuko Hoshino, Julian Petersen, Yuan Guo, Matthew M. Parks, Chad M. Kurylo, Jake E. Batchelder, Kristian Haller, Ayako Hashimoto, Helene Rundqivst, John S. Condeelis, C. David Allis, Denis Drygin, M. Angela Nieto, Michael Andäng, Piergiorgio PercipalleJonas Bergh, Igor Adameyko, Ann Kristin Östlund Farrants, Johan Hartman, David Lyden, Kristian Pietras, Scott C. Blanchard, C. Theresa Vincent

Cell Biology

Research output: Contribution to journal › Article › peer-review

91 Scopus citations

Abstract

Ribosome biogenesis is a canonical hallmark of cell growth and proliferation. Here we show that execution of Epithelial-to-Mesenchymal Transition (EMT), a migratory cellular program associated with development and tumor metastasis, is fueled by upregulation of ribosome biogenesis during G1/S arrest. This unexpected EMT feature is independent of species and initiating signal, and is accompanied by release of the repressive nucleolar chromatin remodeling complex (NoRC) from rDNA, together with recruitment of the EMT-driving transcription factor Snai1 (Snail1), RNA Polymerase I (Pol I) and the Upstream Binding Factor (UBF). EMT-associated ribosome biogenesis is also coincident with increased nucleolar recruitment of Rictor, an essential component of the EMT-promoting mammalian target of rapamycin complex 2 (mTORC2). Inhibition of rRNA synthesis in vivo differentiates primary tumors to a benign, Estrogen Receptor-alpha (ERα) positive, Rictor-negative phenotype and reduces metastasis. These findings implicate the EMT-associated ribosome biogenesis program with cellular plasticity, de-differentiation, cancer progression and metastatic disease.

Original language	English (US)
Article number	2110
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-10100-8
State	Published - Dec 1 2019

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-019-10100-8

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Prakash, V., Carson, B. B., Feenstra, J. M., Dass, R. A., Sekyrova, P., Hoshino, A., Petersen, J., Guo, Y., Parks, M. M., Kurylo, C. M., Batchelder, J. E., Haller, K., Hashimoto, A., Rundqivst, H., Condeelis, J. S., Allis, C. D., Drygin, D., Nieto, M. A., Andäng, M., ... Vincent, C. T. (2019). Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease. Nature communications, 10(1), [2110]. https://doi.org/10.1038/s41467-019-10100-8

Prakash, V, Carson, BB, Feenstra, JM, Dass, RA, Sekyrova, P, Hoshino, A, Petersen, J, Guo, Y, Parks, MM, Kurylo, CM, Batchelder, JE, Haller, K, Hashimoto, A, Rundqivst, H, Condeelis, JS, Allis, CD, Drygin, D, Nieto, MA, Andäng, M, Percipalle, P, Bergh, J, Adameyko, I, Farrants, AKÖ, Hartman, J, Lyden, D, Pietras, K, Blanchard, SC & Vincent, CT 2019, 'Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease', Nature communications, vol. 10, no. 1, 2110. https://doi.org/10.1038/s41467-019-10100-8

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title = "Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease",

abstract = "Ribosome biogenesis is a canonical hallmark of cell growth and proliferation. Here we show that execution of Epithelial-to-Mesenchymal Transition (EMT), a migratory cellular program associated with development and tumor metastasis, is fueled by upregulation of ribosome biogenesis during G1/S arrest. This unexpected EMT feature is independent of species and initiating signal, and is accompanied by release of the repressive nucleolar chromatin remodeling complex (NoRC) from rDNA, together with recruitment of the EMT-driving transcription factor Snai1 (Snail1), RNA Polymerase I (Pol I) and the Upstream Binding Factor (UBF). EMT-associated ribosome biogenesis is also coincident with increased nucleolar recruitment of Rictor, an essential component of the EMT-promoting mammalian target of rapamycin complex 2 (mTORC2). Inhibition of rRNA synthesis in vivo differentiates primary tumors to a benign, Estrogen Receptor-alpha (ERα) positive, Rictor-negative phenotype and reduces metastasis. These findings implicate the EMT-associated ribosome biogenesis program with cellular plasticity, de-differentiation, cancer progression and metastatic disease.",

author = "Varsha Prakash and Carson, {Brittany B.} and Feenstra, {Jennifer M.} and Dass, {Randall A.} and Petra Sekyrova and Ayuko Hoshino and Julian Petersen and Yuan Guo and Parks, {Matthew M.} and Kurylo, {Chad M.} and Batchelder, {Jake E.} and Kristian Haller and Ayako Hashimoto and Helene Rundqivst and Condeelis, {John S.} and Allis, {C. David} and Denis Drygin and Nieto, {M. Angela} and Michael And{\"a}ng and Piergiorgio Percipalle and Jonas Bergh and Igor Adameyko and Farrants, {Ann Kristin {\"O}stlund} and Johan Hartman and David Lyden and Kristian Pietras and Blanchard, {Scott C.} and Vincent, {C. Theresa}",

note = "Funding Information: This work was supported by the Swedish Cancer Society (Cancerfonden), Swedish Research Council (Vetenskapsr{\aa}det, Young Investigator Grant and Project grant), VINNMER–Marie Curie international qualification, Georg and Eva Klein Visiting Junior Scientist Award, Sigurd och Elsa Goljes minne, Magnus Bergvall foundation, Alex and Eva Wallstr{\"o}m foundation, American Scandinavia Foundation (Sverige Amerika Stif-telsen), {\AA}ke Wiberg foundation, Tore Nilsson foundation, the Karolinska Institute funds and IGP, Uppsala University (to C.T.V.). S.C.B, C.T.V, R.A.D. and M.M.P were supported by the Tri-Institutional Stem Cell Initiative funded by the Starr Foundation and the National Institutes of Health (GM079238). P.S. was supported by Cancerfonden postdoctoral fellowship and the Grant Agency of the Czech Republic (GA15-20818S). J.P was supported by the Swedish Research Council (Vetenskapsr{\aa}det). “K.P. is the G{\"o}ran &; Birgitta Grosskopf Professor at Lund University and supported by the ERC Consolidator grant TUMORGAN”. The confocal imaging facility and FACS facility at KI were supported by Knut &; Alice Wallenberg foundation. We also thank R. Altman, Mikael Holm and E. Rundlet, for helpful comments during the preparation of the manuscript. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-10100-8",

language = "English (US)",

volume = "10",

journal = "Nature Communications",

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TY - JOUR

T1 - Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease

AU - Prakash, Varsha

AU - Carson, Brittany B.

AU - Feenstra, Jennifer M.

AU - Dass, Randall A.

AU - Sekyrova, Petra

AU - Hoshino, Ayuko

AU - Petersen, Julian

AU - Guo, Yuan

AU - Parks, Matthew M.

AU - Kurylo, Chad M.

AU - Batchelder, Jake E.

AU - Haller, Kristian

AU - Hashimoto, Ayako

AU - Rundqivst, Helene

AU - Condeelis, John S.

AU - Allis, C. David

AU - Drygin, Denis

AU - Nieto, M. Angela

AU - Andäng, Michael

AU - Percipalle, Piergiorgio

AU - Bergh, Jonas

AU - Adameyko, Igor

AU - Farrants, Ann Kristin Östlund

AU - Hartman, Johan

AU - Lyden, David

AU - Pietras, Kristian

AU - Blanchard, Scott C.

AU - Vincent, C. Theresa

N1 - Funding Information: This work was supported by the Swedish Cancer Society (Cancerfonden), Swedish Research Council (Vetenskapsrådet, Young Investigator Grant and Project grant), VINNMER–Marie Curie international qualification, Georg and Eva Klein Visiting Junior Scientist Award, Sigurd och Elsa Goljes minne, Magnus Bergvall foundation, Alex and Eva Wallström foundation, American Scandinavia Foundation (Sverige Amerika Stif-telsen), Åke Wiberg foundation, Tore Nilsson foundation, the Karolinska Institute funds and IGP, Uppsala University (to C.T.V.). S.C.B, C.T.V, R.A.D. and M.M.P were supported by the Tri-Institutional Stem Cell Initiative funded by the Starr Foundation and the National Institutes of Health (GM079238). P.S. was supported by Cancerfonden postdoctoral fellowship and the Grant Agency of the Czech Republic (GA15-20818S). J.P was supported by the Swedish Research Council (Vetenskapsrådet). “K.P. is the Göran &; Birgitta Grosskopf Professor at Lund University and supported by the ERC Consolidator grant TUMORGAN”. The confocal imaging facility and FACS facility at KI were supported by Knut &; Alice Wallenberg foundation. We also thank R. Altman, Mikael Holm and E. Rundlet, for helpful comments during the preparation of the manuscript. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Ribosome biogenesis is a canonical hallmark of cell growth and proliferation. Here we show that execution of Epithelial-to-Mesenchymal Transition (EMT), a migratory cellular program associated with development and tumor metastasis, is fueled by upregulation of ribosome biogenesis during G1/S arrest. This unexpected EMT feature is independent of species and initiating signal, and is accompanied by release of the repressive nucleolar chromatin remodeling complex (NoRC) from rDNA, together with recruitment of the EMT-driving transcription factor Snai1 (Snail1), RNA Polymerase I (Pol I) and the Upstream Binding Factor (UBF). EMT-associated ribosome biogenesis is also coincident with increased nucleolar recruitment of Rictor, an essential component of the EMT-promoting mammalian target of rapamycin complex 2 (mTORC2). Inhibition of rRNA synthesis in vivo differentiates primary tumors to a benign, Estrogen Receptor-alpha (ERα) positive, Rictor-negative phenotype and reduces metastasis. These findings implicate the EMT-associated ribosome biogenesis program with cellular plasticity, de-differentiation, cancer progression and metastatic disease.

AB - Ribosome biogenesis is a canonical hallmark of cell growth and proliferation. Here we show that execution of Epithelial-to-Mesenchymal Transition (EMT), a migratory cellular program associated with development and tumor metastasis, is fueled by upregulation of ribosome biogenesis during G1/S arrest. This unexpected EMT feature is independent of species and initiating signal, and is accompanied by release of the repressive nucleolar chromatin remodeling complex (NoRC) from rDNA, together with recruitment of the EMT-driving transcription factor Snai1 (Snail1), RNA Polymerase I (Pol I) and the Upstream Binding Factor (UBF). EMT-associated ribosome biogenesis is also coincident with increased nucleolar recruitment of Rictor, an essential component of the EMT-promoting mammalian target of rapamycin complex 2 (mTORC2). Inhibition of rRNA synthesis in vivo differentiates primary tumors to a benign, Estrogen Receptor-alpha (ERα) positive, Rictor-negative phenotype and reduces metastasis. These findings implicate the EMT-associated ribosome biogenesis program with cellular plasticity, de-differentiation, cancer progression and metastatic disease.

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JO - Nature Communications

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ER -

Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease

Abstract

ASJC Scopus subject areas

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