Isoform-specific deletion of PKM2 constrains tumor initiation in a mouse model of soft tissue sarcoma
Background Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of the glycolytic enzyme pyruvate kinase. PKM2 expression is associated with embryogenesis, tissue regeneration, and cancer. PKM2 is also the pyruvate kinase isoform expressed in most wild-t...
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| Format: | Article |
| Language: | English |
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BioMed Central Ltd.
2018
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| Online Access: | http://hdl.handle.net/1721.1/116108 https://orcid.org/0000-0002-7994-7963 https://orcid.org/0000-0002-7799-6454 https://orcid.org/0000-0002-6883-3805 https://orcid.org/0000-0002-6702-4192 https://orcid.org/0000-0001-5785-8911 |
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| author | Dayton, Talya L. Miller, Kathryn M. Bronson, Roderick T. Dayton, Talya L. Gocheva, Vasilena Miller, Kathryn Bhutkar, Arjun Chidley, Caroline Vander Heiden, Matthew G. Jacks, Tyler E. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Dayton, Talya L. Miller, Kathryn M. Bronson, Roderick T. Dayton, Talya L. Gocheva, Vasilena Miller, Kathryn Bhutkar, Arjun Chidley, Caroline Vander Heiden, Matthew G. Jacks, Tyler E. |
| author_sort | Dayton, Talya L. |
| collection | MIT |
| description | Background
Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of the glycolytic enzyme pyruvate kinase. PKM2 expression is associated with embryogenesis, tissue regeneration, and cancer. PKM2 is also the pyruvate kinase isoform expressed in most wild-type adult tissues, with PKM1 restricted primarily to skeletal muscle, heart, and brain. To interrogate the functional requirement for PKM2 during tumor initiation in an autochthonous mouse model for soft tissue sarcoma (STS), we used a conditional Pkm2 allele (Pkm2[superscript fl]) to abolish PKM2 expression.
Results
PKM2 deletion slowed tumor onset but did not abrogate eventual tumor outgrowth. PKM2-null sarcoma cells expressed PKM1 with tumors containing a high number of infiltrating PKM2 expressing stromal cells. End-stage PKM2-null tumors showed increased proliferation compared to tumors with a wild-type Pkm2 allele, and tumor metabolite analysis revealed metabolic changes associated with PKM2 loss.
Conclusions
While PKM2 is not required for soft tissue sarcoma growth, PKM2 expression may facilitate initiation of this tumor type. Because these data differ from what has been observed in other cancer models where PKM2 has been deleted, they argue that the consequences of PKM2 loss during tumor initiation are dependent on the tumor type. Keywords: PKM2; Soft tissue sarcoma;Cancer |
| first_indexed | 2024-09-23T17:15:07Z |
| format | Article |
| id | mit-1721.1/116108 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T17:15:07Z |
| publishDate | 2018 |
| publisher | BioMed Central Ltd. |
| record_format | dspace |
| spelling | mit-1721.1/1161082022-09-30T00:44:40Z Isoform-specific deletion of PKM2 constrains tumor initiation in a mouse model of soft tissue sarcoma Dayton, Talya L. Miller, Kathryn M. Bronson, Roderick T. Dayton, Talya L. Gocheva, Vasilena Miller, Kathryn Bhutkar, Arjun Chidley, Caroline Vander Heiden, Matthew G. Jacks, Tyler E. Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Dayton, Talya L. Gocheva, Vasilena Miller, Kathryn Bhutkar, Arjun Chidley, Caroline Vander Heiden, Matthew G. Jacks, Tyler E. Background Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of the glycolytic enzyme pyruvate kinase. PKM2 expression is associated with embryogenesis, tissue regeneration, and cancer. PKM2 is also the pyruvate kinase isoform expressed in most wild-type adult tissues, with PKM1 restricted primarily to skeletal muscle, heart, and brain. To interrogate the functional requirement for PKM2 during tumor initiation in an autochthonous mouse model for soft tissue sarcoma (STS), we used a conditional Pkm2 allele (Pkm2[superscript fl]) to abolish PKM2 expression. Results PKM2 deletion slowed tumor onset but did not abrogate eventual tumor outgrowth. PKM2-null sarcoma cells expressed PKM1 with tumors containing a high number of infiltrating PKM2 expressing stromal cells. End-stage PKM2-null tumors showed increased proliferation compared to tumors with a wild-type Pkm2 allele, and tumor metabolite analysis revealed metabolic changes associated with PKM2 loss. Conclusions While PKM2 is not required for soft tissue sarcoma growth, PKM2 expression may facilitate initiation of this tumor type. Because these data differ from what has been observed in other cancer models where PKM2 has been deleted, they argue that the consequences of PKM2 loss during tumor initiation are dependent on the tumor type. Keywords: PKM2; Soft tissue sarcoma;Cancer National Cancer Institute (U.S.) (Grant P30CA14051) 2018-06-05T17:50:28Z 2018-06-05T17:50:28Z 2018-05 2018-02 2018-06-03T04:02:24Z Article http://purl.org/eprint/type/JournalArticle 2049-3002 http://hdl.handle.net/1721.1/116108 Dayton, Talya L. et al. "Isoform-specific deletion of PKM2 constrains tumor initiation in a mouse model of soft tissue sarcoma." Cancer & Metabolism 2018, 6 (May 2018): 6 © 2018 The Author(s) https://orcid.org/0000-0002-7994-7963 https://orcid.org/0000-0002-7799-6454 https://orcid.org/0000-0002-6883-3805 https://orcid.org/0000-0002-6702-4192 https://orcid.org/0000-0001-5785-8911 en https://doi.org/10.1186/s40170-018-0179-2 Cancer & Metabolism Creative Commons Attribution http://creativecommons.org/licenses/by/4.0/ The Author(s). application/pdf BioMed Central Ltd. BioMed Central |
| spellingShingle | Dayton, Talya L. Miller, Kathryn M. Bronson, Roderick T. Dayton, Talya L. Gocheva, Vasilena Miller, Kathryn Bhutkar, Arjun Chidley, Caroline Vander Heiden, Matthew G. Jacks, Tyler E. Isoform-specific deletion of PKM2 constrains tumor initiation in a mouse model of soft tissue sarcoma |
| title | Isoform-specific deletion of PKM2 constrains tumor initiation in a mouse model of soft tissue sarcoma |
| title_full | Isoform-specific deletion of PKM2 constrains tumor initiation in a mouse model of soft tissue sarcoma |
| title_fullStr | Isoform-specific deletion of PKM2 constrains tumor initiation in a mouse model of soft tissue sarcoma |
| title_full_unstemmed | Isoform-specific deletion of PKM2 constrains tumor initiation in a mouse model of soft tissue sarcoma |
| title_short | Isoform-specific deletion of PKM2 constrains tumor initiation in a mouse model of soft tissue sarcoma |
| title_sort | isoform specific deletion of pkm2 constrains tumor initiation in a mouse model of soft tissue sarcoma |
| url | http://hdl.handle.net/1721.1/116108 https://orcid.org/0000-0002-7994-7963 https://orcid.org/0000-0002-7799-6454 https://orcid.org/0000-0002-6883-3805 https://orcid.org/0000-0002-6702-4192 https://orcid.org/0000-0001-5785-8911 |
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