Cargando…

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-type adult tissue...

Descripción completa

Detalles Bibliográficos
Autores principales: Dayton, Talya L., Gocheva, Vasilena, Miller, Kathryn M., Bhutkar, Arjun, Lewis, Caroline A., Bronson, Roderick T., Vander Heiden, Matthew G., Jacks, Tyler
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977456/
https://www.ncbi.nlm.nih.gov/pubmed/29854399
http://dx.doi.org/10.1186/s40170-018-0179-2
_version_ 1783327381666136064
author Dayton, Talya L.
Gocheva, Vasilena
Miller, Kathryn M.
Bhutkar, Arjun
Lewis, Caroline A.
Bronson, Roderick T.
Vander Heiden, Matthew G.
Jacks, Tyler
author_facet Dayton, Talya L.
Gocheva, Vasilena
Miller, Kathryn M.
Bhutkar, Arjun
Lewis, Caroline A.
Bronson, Roderick T.
Vander Heiden, Matthew G.
Jacks, Tyler
author_sort Dayton, Talya L.
collection PubMed
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(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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40170-018-0179-2) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-5977456
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-59774562018-05-31 Isoform-specific deletion of PKM2 constrains tumor initiation in a mouse model of soft tissue sarcoma Dayton, Talya L. Gocheva, Vasilena Miller, Kathryn M. Bhutkar, Arjun Lewis, Caroline A. Bronson, Roderick T. Vander Heiden, Matthew G. Jacks, Tyler Cancer Metab Research 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(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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40170-018-0179-2) contains supplementary material, which is available to authorized users. BioMed Central 2018-05-31 /pmc/articles/PMC5977456/ /pubmed/29854399 http://dx.doi.org/10.1186/s40170-018-0179-2 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Dayton, Talya L.
Gocheva, Vasilena
Miller, Kathryn M.
Bhutkar, Arjun
Lewis, Caroline A.
Bronson, Roderick T.
Vander Heiden, Matthew G.
Jacks, Tyler
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
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977456/
https://www.ncbi.nlm.nih.gov/pubmed/29854399
http://dx.doi.org/10.1186/s40170-018-0179-2
work_keys_str_mv AT daytontalyal isoformspecificdeletionofpkm2constrainstumorinitiationinamousemodelofsofttissuesarcoma
AT gochevavasilena isoformspecificdeletionofpkm2constrainstumorinitiationinamousemodelofsofttissuesarcoma
AT millerkathrynm isoformspecificdeletionofpkm2constrainstumorinitiationinamousemodelofsofttissuesarcoma
AT bhutkararjun isoformspecificdeletionofpkm2constrainstumorinitiationinamousemodelofsofttissuesarcoma
AT lewiscarolinea isoformspecificdeletionofpkm2constrainstumorinitiationinamousemodelofsofttissuesarcoma
AT bronsonroderickt isoformspecificdeletionofpkm2constrainstumorinitiationinamousemodelofsofttissuesarcoma
AT vanderheidenmatthewg isoformspecificdeletionofpkm2constrainstumorinitiationinamousemodelofsofttissuesarcoma
AT jackstyler isoformspecificdeletionofpkm2constrainstumorinitiationinamousemodelofsofttissuesarcoma