Developing analytical tools to investigate the role of translation in homeostasis and disease
Author: Oertlin, Christian
Date: 2021-04-23
Location: Online or limited spaces: Room Becquerel, Gamma 5, SciLifeLab, Tomtebodavägen 23, Solna
Time: 13.00
Department: Inst för onkologi-patologi / Dept of Oncology-Pathology
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Thesis (2.107Mb)
Abstract
Transcriptome-wide studies of translation efficiencies are required to improve understanding of translational regulation and its role in homeostatic mechanisms. In Study 1, we developed an algorithm for analysis of translation efficiency, called anota2seq. We show that anota2seq outperforms current methodologies and, due to its unique analytical approach, it is the only method to statistically distinguish important modes for regulation of gene expression, i.e translation and translational buffering.
Pancreatic cancer is a lethal malignancy with very limited treatment options. In Study 2, we evaluate the impact of using an eIF4A inhibitor, CR-31, on mRNA translation in pancreatic cancer. eIF4A is a component of the eIF4F translation initiation complex. We show that inhibiting eIF4A in murine and human pancreatic ductal adenocarcinoma (PDAC) models induces an energy crisis by impacting translation of mRNAs related to oxidative phosphorylation and glycolysis. This leads to the shift of metabolic dependency of PDACs towards reductive glutamine metabolism. Exploiting the dependence on reductive glutamine metabolism using a combined treatment of eIF4A and glutaminase inhibitors revealed an exciting therapeutic treatment strategy for PDAC that did not affect healthy cells.
In Study 3, we investigated the effects of insulin on gene expression in malignant and non-malignant cells. This revealed that malignant cells modulate total mRNA levels differently in response to insulin compared to non-malignant cells, whereas in both translation was dependent on mammalian/mechanistic target of rapamycin (mTOR). However, mTOR inhibition during insulin stimulation in malignant cells lead to translational offsetting of alterations in total mRNA levels. Comparing the effects of mTOR inhibition in malignant cells to that of hypoxia in stem cells revealed that these vastly different cell types share the ability to translationally offset mRNAs. Collectively, these studies improved analysis of translational efficiencies and contributed to advanced understanding of the role of translational dysregulation in cancer.
Pancreatic cancer is a lethal malignancy with very limited treatment options. In Study 2, we evaluate the impact of using an eIF4A inhibitor, CR-31, on mRNA translation in pancreatic cancer. eIF4A is a component of the eIF4F translation initiation complex. We show that inhibiting eIF4A in murine and human pancreatic ductal adenocarcinoma (PDAC) models induces an energy crisis by impacting translation of mRNAs related to oxidative phosphorylation and glycolysis. This leads to the shift of metabolic dependency of PDACs towards reductive glutamine metabolism. Exploiting the dependence on reductive glutamine metabolism using a combined treatment of eIF4A and glutaminase inhibitors revealed an exciting therapeutic treatment strategy for PDAC that did not affect healthy cells.
In Study 3, we investigated the effects of insulin on gene expression in malignant and non-malignant cells. This revealed that malignant cells modulate total mRNA levels differently in response to insulin compared to non-malignant cells, whereas in both translation was dependent on mammalian/mechanistic target of rapamycin (mTOR). However, mTOR inhibition during insulin stimulation in malignant cells lead to translational offsetting of alterations in total mRNA levels. Comparing the effects of mTOR inhibition in malignant cells to that of hypoxia in stem cells revealed that these vastly different cell types share the ability to translationally offset mRNAs. Collectively, these studies improved analysis of translational efficiencies and contributed to advanced understanding of the role of translational dysregulation in cancer.
List of papers:
I. Oertlin Christian, Lorent Julie, Murie Carl, Furic Luc, Topisirovic Ivan & Larsson Ola. (2019). Generally applicable transcriptome-wide analysis of translation using anota2seq. Nucleic acids research. 47.
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II. Chan Karina†, Robert Francis†, Oertlin Christian†, Kapeller-Libermann Dana†, Avizonis Daina, Gutierrez Johana, Handly-Santana Abram, Doubrovin Mikhail, Park Julia, Schoepfer Christina, Silva Brandon, Yao Melissa, Gorton Faith, Shi Junwei, Thomas Craig, Brown Lauren, Porco John, Pollak Michael, Larsson Ola & Chio Iok In Christine. (2019). eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma. Nature Communications. 10. 5151. †Equal contribution.
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III. Oertlin Christian†, Ristau Johannes†, Kim Hayley, Tandoc Kristofferson, Mclaughlan Shannon, Gandin Valentina, Masvidal Laia, Cargnello Marie, Szkop Krzysztof, Chen Shan, Watt Kathleen, Lee Laura, Liang Shuo, Mermelakas Georgios, Lethiö Janne, Postovit Lynne-Marie, Furic Luc, Topisirovic Ivan and Larsson Ola. †Equal contribution. [Manuscript]
I. Oertlin Christian, Lorent Julie, Murie Carl, Furic Luc, Topisirovic Ivan & Larsson Ola. (2019). Generally applicable transcriptome-wide analysis of translation using anota2seq. Nucleic acids research. 47.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Chan Karina†, Robert Francis†, Oertlin Christian†, Kapeller-Libermann Dana†, Avizonis Daina, Gutierrez Johana, Handly-Santana Abram, Doubrovin Mikhail, Park Julia, Schoepfer Christina, Silva Brandon, Yao Melissa, Gorton Faith, Shi Junwei, Thomas Craig, Brown Lauren, Porco John, Pollak Michael, Larsson Ola & Chio Iok In Christine. (2019). eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma. Nature Communications. 10. 5151. †Equal contribution.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Oertlin Christian†, Ristau Johannes†, Kim Hayley, Tandoc Kristofferson, Mclaughlan Shannon, Gandin Valentina, Masvidal Laia, Cargnello Marie, Szkop Krzysztof, Chen Shan, Watt Kathleen, Lee Laura, Liang Shuo, Mermelakas Georgios, Lethiö Janne, Postovit Lynne-Marie, Furic Luc, Topisirovic Ivan and Larsson Ola. †Equal contribution. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Larsson, Ola
Co-supervisor: Topisirovic, Ivan
Issue date: 2021-03-31
Rights:
Publication year: 2021
ISBN: 978-91-8016-202-9
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