Exploring mTOR-dependent regulation of mRNA translation in cancer
Author: Liu, Hui
Date: 2021-06-23
Location: ScilifeLab Gamma5, G5201 Becquerel, Solna
Time: 13.00
Department: Inst för onkologi-patologi / Dept of Oncology-Pathology
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Thesis (2.139Mb)
Abstract
Modulation of mRNA translation via the mammalian target of rapamycin (mTOR) pathway is primarily achieved by integrating internal or external signals onto the translation machinery, especially on the rate-limiting initiation step during mRNA translation. Subsets of transcripts are discriminated by structural and/or sequence features, and encode proteins involved in different biological functions. For example, a group of mRNAs with a stretch of uninterrupted 4-15 pyrimidines following a cytosine after the m7Gppp cap at their 5’ untranslated region (5’UTR) are termed as TOP mRNAs, which mainly encode ribosomal proteins and translation factors. By developing a luciferase reporter to quantify TOP mRNA translation, this thesis provides insight into mTOR-dependent or -independent modulators of TOP mRNA translation. These studies also suggest a vast kinase repertoire potentially modulating TOP-mRNA translation (Paper II).
Aberrations in mTOR pathway drive tumorigenesis and development. The first-generation allosteric mTOR inhibitors, rapamycin analogs (also called rapalogs), and the second generation ATP-competitive kinase mTOR inhibitors have been tested in a wide range of tumors as monotherapy or a component of combination therapy. However, either the poor potency of the first generation or the toxicity of the second generation makes the clinical benefit limited. Based on the prototype of one third-generation mTOR inhibitor, RapaLink-1, we produced a series of new mTORC1-selective bi-steric inhibitors through continuous and finely tuned pharmaceutical and chemical modifications, which selectively inhibit mTORC1 over mTORC2, but retain potent efficacy in suppressing tumor growth (Paper I). Findings within Paper I demonstrate that mTORC1 mediates modulation of mRNA translation.
Immune cells within the tumor microenvironment (TME) represent an indispensable factor during tumor cells’ escape from immune surveillance, which occurs via multiple mechanisms, including immune cell acquisition of pro-tumor phenotypes. Therefore, immunotherapy, which re-activates the immune system towards cancer cells, has emerged as an essential treatment option. Paper IV indicates that immune suppression mediated by tumor-associated macrophage (TAM) depends on the MNK2/eIF4E axis but not mTOR. The model suggests that MNK2 thereby controls translation of a subset of transcripts encoding proteins which in turn modulate the TAM phenotype. This finding extends our understanding of how mRNA translation contributes to immune cell phenotypes.
Expression of a functional Von Hippel-Lindau Tumor Suppressor (VHL) protein is commonly lost in renal cell carcinoma (RCC). In RCC, there is ample prognosis heterogeneity among patients treated with rapalogs, which inhibits mTORC1. Thus, it could be due to acquired resistance. Therefore, We examined whether alterations in gene expression in response to rapalogs associated with VHL status (Paper III). As expected, VHL re-expression not only caused wide-spread changes in mRNA levels but also alterations in mRNA translation. Moreover, translation of transcripts subsets was sensitive to rapamycin only under VHL proficiency or VHL deficiency. Further studies will aim to determine whether these differences affect downstream phenotypes.
Aberrations in mTOR pathway drive tumorigenesis and development. The first-generation allosteric mTOR inhibitors, rapamycin analogs (also called rapalogs), and the second generation ATP-competitive kinase mTOR inhibitors have been tested in a wide range of tumors as monotherapy or a component of combination therapy. However, either the poor potency of the first generation or the toxicity of the second generation makes the clinical benefit limited. Based on the prototype of one third-generation mTOR inhibitor, RapaLink-1, we produced a series of new mTORC1-selective bi-steric inhibitors through continuous and finely tuned pharmaceutical and chemical modifications, which selectively inhibit mTORC1 over mTORC2, but retain potent efficacy in suppressing tumor growth (Paper I). Findings within Paper I demonstrate that mTORC1 mediates modulation of mRNA translation.
Immune cells within the tumor microenvironment (TME) represent an indispensable factor during tumor cells’ escape from immune surveillance, which occurs via multiple mechanisms, including immune cell acquisition of pro-tumor phenotypes. Therefore, immunotherapy, which re-activates the immune system towards cancer cells, has emerged as an essential treatment option. Paper IV indicates that immune suppression mediated by tumor-associated macrophage (TAM) depends on the MNK2/eIF4E axis but not mTOR. The model suggests that MNK2 thereby controls translation of a subset of transcripts encoding proteins which in turn modulate the TAM phenotype. This finding extends our understanding of how mRNA translation contributes to immune cell phenotypes.
Expression of a functional Von Hippel-Lindau Tumor Suppressor (VHL) protein is commonly lost in renal cell carcinoma (RCC). In RCC, there is ample prognosis heterogeneity among patients treated with rapalogs, which inhibits mTORC1. Thus, it could be due to acquired resistance. Therefore, We examined whether alterations in gene expression in response to rapalogs associated with VHL status (Paper III). As expected, VHL re-expression not only caused wide-spread changes in mRNA levels but also alterations in mRNA translation. Moreover, translation of transcripts subsets was sensitive to rapamycin only under VHL proficiency or VHL deficiency. Further studies will aim to determine whether these differences affect downstream phenotypes.
List of papers:
I. Selective Inhibitors of mTORC1 Activate 4EBP1 and Suppress Tumor Growth. Bianca J. Lee*, Jacob A. Boyer*, G. Leslie Burnett, Arun P. Thottumkara, Nidhi Tibrewal, Stacy L. Wilson, Tientien Hsieh, Abby Marquez, Edward G. Lorenzana, James W. Evans, Laura Hulea, Gert Kiss, Hui Liu, Dong Lee, Ola Larsson, Shannon McLaughlan, Ivan Topisirovic, Zhengping Wang, Zhican Wang, Yongyuan Zhao, David Wildes, James B. Aggen, Mallika Singh, Adrian L. Gill, Jacqueline A. M. Smith#, Neal Rosen#. *Equal contributions, #Corresponding authors. [Accepted]
Fulltext (DOI)
Pubmed
II. Identification of kinases modulating translation of mRNAs with terminal oligo-pyrimidine (TOP) motifs. Hui Liu, Vincent van Hoef, Johannes Ristau, and Ola Larsson. [Manuscript]
III. In vitro characterization of VHL dependent mRNA translation in renal cell carcinoma. Hui Liu*, Julia Vassalakis*, Kathleen Watt, Kristofferson Tandoc, Fernanda C S Lupinacci, Shannon McLaughlan, Martín Roffé, Ola Larsson#, Ivan Topisirovic#, Glaucia N.M. Hajj#. *Equal contributions. #Corresponding authors. [Manuscript]
IV. MNK2 governs the macrophage antiinflammatory phenotype. Margarita Bartish*, Dongmei Tong*,Yangxun Pan, Majken Wallerius, Hui Liu, Johannes Ristau, Sabrina de Souza Ferreira, Tatjana Wallmann, Vincent van Hoef, Laia Masvidal, Thomas Kerzel, Anne-Laure Joly, Christophe Goncalves, Samuel E. J. Preston, Talin Ebrahimian, Christina Seitz, Jonas Bergh, Kristian Pietras, Stephanie Lehoux, Luigi Naldini, John Andersson, Mario Leonardo Squadrito, Sonia V. del Rincón, Ola Larsson#, and Charlotte Rolny#. PNAS. 2020 Nov 3;117(44):27556-27565. *Equal contributions, #Corresponding authors.
Fulltext (DOI)
Pubmed
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I. Selective Inhibitors of mTORC1 Activate 4EBP1 and Suppress Tumor Growth. Bianca J. Lee*, Jacob A. Boyer*, G. Leslie Burnett, Arun P. Thottumkara, Nidhi Tibrewal, Stacy L. Wilson, Tientien Hsieh, Abby Marquez, Edward G. Lorenzana, James W. Evans, Laura Hulea, Gert Kiss, Hui Liu, Dong Lee, Ola Larsson, Shannon McLaughlan, Ivan Topisirovic, Zhengping Wang, Zhican Wang, Yongyuan Zhao, David Wildes, James B. Aggen, Mallika Singh, Adrian L. Gill, Jacqueline A. M. Smith#, Neal Rosen#. *Equal contributions, #Corresponding authors. [Accepted]
Fulltext (DOI)
Pubmed
II. Identification of kinases modulating translation of mRNAs with terminal oligo-pyrimidine (TOP) motifs. Hui Liu, Vincent van Hoef, Johannes Ristau, and Ola Larsson. [Manuscript]
III. In vitro characterization of VHL dependent mRNA translation in renal cell carcinoma. Hui Liu*, Julia Vassalakis*, Kathleen Watt, Kristofferson Tandoc, Fernanda C S Lupinacci, Shannon McLaughlan, Martín Roffé, Ola Larsson#, Ivan Topisirovic#, Glaucia N.M. Hajj#. *Equal contributions. #Corresponding authors. [Manuscript]
IV. MNK2 governs the macrophage antiinflammatory phenotype. Margarita Bartish*, Dongmei Tong*,Yangxun Pan, Majken Wallerius, Hui Liu, Johannes Ristau, Sabrina de Souza Ferreira, Tatjana Wallmann, Vincent van Hoef, Laia Masvidal, Thomas Kerzel, Anne-Laure Joly, Christophe Goncalves, Samuel E. J. Preston, Talin Ebrahimian, Christina Seitz, Jonas Bergh, Kristian Pietras, Stephanie Lehoux, Luigi Naldini, John Andersson, Mario Leonardo Squadrito, Sonia V. del Rincón, Ola Larsson#, and Charlotte Rolny#. PNAS. 2020 Nov 3;117(44):27556-27565. *Equal contributions, #Corresponding authors.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Larsson, Ola
Co-supervisor: Rolny, Charlotte
Issue date: 2021-06-01
Rights:
Publication year: 2021
ISBN: 978-91-8016-249-4
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