Tissue of origin dictates GOT1 dependence and confers synthetic lethality to radiotherapy
Abstract Background Metabolic programs in cancer cells are influenced by genotype and the tissue of origin. We have previously shown that central carbon metabolism is rewired in pancreatic ductal adenocarcinoma (PDA) to support proliferation through a glutamate oxaloacetate transaminase 1 (GOT1)-dep...
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BMC
2020-01-01
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Series: | Cancer & Metabolism |
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Online Access: | https://doi.org/10.1186/s40170-019-0202-2 |
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doaj-e08285467c004f0193e607f0286f4ab7 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Barbara S. Nelson Lin Lin Daniel M. Kremer Cristovão M. Sousa Cecilia Cotta-Ramusino Amy Myers Johanna Ramos Tina Gao Ilya Kovalenko Kari Wilder-Romans Joseph Dresser Mary Davis Ho-Joon Lee Zeribe C. Nwosu Scott Campit Oksana Mashadova Brandon N. Nicolay Zachary P. Tolstyka Christopher J. Halbrook Sriram Chandrasekaran John M. Asara Howard C. Crawford Lewis C. Cantley Alec C. Kimmelman Daniel R. Wahl Costas A. Lyssiotis |
spellingShingle |
Barbara S. Nelson Lin Lin Daniel M. Kremer Cristovão M. Sousa Cecilia Cotta-Ramusino Amy Myers Johanna Ramos Tina Gao Ilya Kovalenko Kari Wilder-Romans Joseph Dresser Mary Davis Ho-Joon Lee Zeribe C. Nwosu Scott Campit Oksana Mashadova Brandon N. Nicolay Zachary P. Tolstyka Christopher J. Halbrook Sriram Chandrasekaran John M. Asara Howard C. Crawford Lewis C. Cantley Alec C. Kimmelman Daniel R. Wahl Costas A. Lyssiotis Tissue of origin dictates GOT1 dependence and confers synthetic lethality to radiotherapy Cancer & Metabolism Metabolomics Stable isotope tracing Fluxomics Pancreatic cancer PDA Colorectal cancer |
author_facet |
Barbara S. Nelson Lin Lin Daniel M. Kremer Cristovão M. Sousa Cecilia Cotta-Ramusino Amy Myers Johanna Ramos Tina Gao Ilya Kovalenko Kari Wilder-Romans Joseph Dresser Mary Davis Ho-Joon Lee Zeribe C. Nwosu Scott Campit Oksana Mashadova Brandon N. Nicolay Zachary P. Tolstyka Christopher J. Halbrook Sriram Chandrasekaran John M. Asara Howard C. Crawford Lewis C. Cantley Alec C. Kimmelman Daniel R. Wahl Costas A. Lyssiotis |
author_sort |
Barbara S. Nelson |
title |
Tissue of origin dictates GOT1 dependence and confers synthetic lethality to radiotherapy |
title_short |
Tissue of origin dictates GOT1 dependence and confers synthetic lethality to radiotherapy |
title_full |
Tissue of origin dictates GOT1 dependence and confers synthetic lethality to radiotherapy |
title_fullStr |
Tissue of origin dictates GOT1 dependence and confers synthetic lethality to radiotherapy |
title_full_unstemmed |
Tissue of origin dictates GOT1 dependence and confers synthetic lethality to radiotherapy |
title_sort |
tissue of origin dictates got1 dependence and confers synthetic lethality to radiotherapy |
publisher |
BMC |
series |
Cancer & Metabolism |
issn |
2049-3002 |
publishDate |
2020-01-01 |
description |
Abstract Background Metabolic programs in cancer cells are influenced by genotype and the tissue of origin. We have previously shown that central carbon metabolism is rewired in pancreatic ductal adenocarcinoma (PDA) to support proliferation through a glutamate oxaloacetate transaminase 1 (GOT1)-dependent pathway. Methods We utilized a doxycycline-inducible shRNA-mediated strategy to knockdown GOT1 in PDA and colorectal cancer (CRC) cell lines and tumor models of similar genotype. These cells were analyzed for the ability to form colonies and tumors to test if tissue type impacted GOT1 dependence. Additionally, the ability of GOT1 to impact the response to chemo- and radiotherapy was assessed. Mechanistically, the associated specimens were examined using a combination of steady-state and stable isotope tracing metabolomics strategies and computational modeling. Statistics were calculated using GraphPad Prism 7. One-way ANOVA was performed for experiments comparing multiple groups with one changing variable. Student’s t test (unpaired, two-tailed) was performed when comparing two groups to each other. Metabolomics data comparing three PDA and three CRC cell lines were analyzed by performing Student’s t test (unpaired, two-tailed) between all PDA metabolites and CRC metabolites. Results While PDA exhibits profound growth inhibition upon GOT1 knockdown, we found CRC to be insensitive. In PDA, but not CRC, GOT1 inhibition disrupted glycolysis, nucleotide metabolism, and redox homeostasis. These insights were leveraged in PDA, where we demonstrate that radiotherapy potently enhanced the effect of GOT1 inhibition on tumor growth. Conclusions Taken together, these results illustrate the role of tissue type in dictating metabolic dependencies and provide new insights for targeting metabolism to treat PDA. |
topic |
Metabolomics Stable isotope tracing Fluxomics Pancreatic cancer PDA Colorectal cancer |
url |
https://doi.org/10.1186/s40170-019-0202-2 |
work_keys_str_mv |
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doaj-e08285467c004f0193e607f0286f4ab72021-01-03T12:05:37ZengBMCCancer & Metabolism2049-30022020-01-018111610.1186/s40170-019-0202-2Tissue of origin dictates GOT1 dependence and confers synthetic lethality to radiotherapyBarbara S. NelsonLin LinDaniel M. Kremer0Cristovão M. Sousa1Cecilia Cotta-Ramusino2Amy Myers3Johanna Ramos4Tina Gao5Ilya Kovalenko6Kari Wilder-Romans7Joseph Dresser8Mary Davis9Ho-Joon Lee10Zeribe C. Nwosu11Scott Campit12Oksana Mashadova13Brandon N. Nicolay14Zachary P. Tolstyka15Christopher J. Halbrook16Sriram Chandrasekaran17John M. Asara18Howard C. Crawford19Lewis C. Cantley20Alec C. Kimmelman21Daniel R. Wahl22Costas A. Lyssiotis23Department of Molecular and Integrative Physiology, University of Michigan Medical SchoolDivision of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolExperimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical SchoolDepartment of Molecular and Integrative Physiology, University of Michigan Medical SchoolDepartment of Molecular and Integrative Physiology, University of Michigan Medical SchoolDepartment of Molecular and Integrative Physiology, University of Michigan Medical SchoolDepartment of Molecular and Integrative Physiology, University of Michigan Medical SchoolDepartment of Radiation Oncology, University of Michigan Medical SchoolDepartment of Radiation Oncology, University of Michigan Medical SchoolDepartment of Radiation Oncology, University of Michigan Medical SchoolDepartment of Molecular and Integrative Physiology, University of Michigan Medical SchoolDepartment of Molecular and Integrative Physiology, University of Michigan Medical SchoolDepartment of Biomedical Engineering, University of Michigan Medical SchoolMeyer Cancer Center, Weill Cornell MedicineAgios Pharmaceuticals, Inc.Department of Molecular and Integrative Physiology, University of Michigan Medical SchoolDepartment of Molecular and Integrative Physiology, University of Michigan Medical SchoolDepartment of Biomedical Engineering, University of Michigan Medical SchoolBeth Israel Deaconess Medical Center and Harvard Medical SchoolDepartment of Molecular and Integrative Physiology, University of Michigan Medical SchoolMeyer Cancer Center, Weill Cornell MedicineDivision of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolDepartment of Radiation Oncology, University of Michigan Medical SchoolDepartment of Molecular and Integrative Physiology, University of Michigan Medical SchoolAbstract Background Metabolic programs in cancer cells are influenced by genotype and the tissue of origin. We have previously shown that central carbon metabolism is rewired in pancreatic ductal adenocarcinoma (PDA) to support proliferation through a glutamate oxaloacetate transaminase 1 (GOT1)-dependent pathway. Methods We utilized a doxycycline-inducible shRNA-mediated strategy to knockdown GOT1 in PDA and colorectal cancer (CRC) cell lines and tumor models of similar genotype. These cells were analyzed for the ability to form colonies and tumors to test if tissue type impacted GOT1 dependence. Additionally, the ability of GOT1 to impact the response to chemo- and radiotherapy was assessed. Mechanistically, the associated specimens were examined using a combination of steady-state and stable isotope tracing metabolomics strategies and computational modeling. Statistics were calculated using GraphPad Prism 7. One-way ANOVA was performed for experiments comparing multiple groups with one changing variable. Student’s t test (unpaired, two-tailed) was performed when comparing two groups to each other. Metabolomics data comparing three PDA and three CRC cell lines were analyzed by performing Student’s t test (unpaired, two-tailed) between all PDA metabolites and CRC metabolites. Results While PDA exhibits profound growth inhibition upon GOT1 knockdown, we found CRC to be insensitive. In PDA, but not CRC, GOT1 inhibition disrupted glycolysis, nucleotide metabolism, and redox homeostasis. These insights were leveraged in PDA, where we demonstrate that radiotherapy potently enhanced the effect of GOT1 inhibition on tumor growth. Conclusions Taken together, these results illustrate the role of tissue type in dictating metabolic dependencies and provide new insights for targeting metabolism to treat PDA.https://doi.org/10.1186/s40170-019-0202-2MetabolomicsStable isotope tracingFluxomicsPancreatic cancerPDAColorectal cancer |