Cargando…

Twist1 Suppresses Senescence Programs and Thereby Accelerates and Maintains Mutant Kras-Induced Lung Tumorigenesis

KRAS mutant lung cancers are generally refractory to chemotherapy as well targeted agents. To date, the identification of drugs to therapeutically inhibit K-RAS have been unsuccessful, suggesting that other approaches are required. We demonstrate in both a novel transgenic mutant Kras lung cancer mo...

Descripción completa

Detalles Bibliográficos
Autores principales: Tran, Phuoc T., Shroff, Emelyn H., Burns, Timothy F., Thiyagarajan, Saravanan, Das, Sandhya T., Zabuawala, Tahera, Chen, Joy, Cho, Yoon-Jae, Luong, Richard, Tamayo, Pablo, Salih, Tarek, Aziz, Khaled, Adam, Stacey J., Vicent, Silvestre, Nielsen, Carsten H., Withofs, Nadia, Sweet-Cordero, Alejandro, Gambhir, Sanjiv S., Rudin, Charles M., Felsher, Dean W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3360067/
https://www.ncbi.nlm.nih.gov/pubmed/22654667
http://dx.doi.org/10.1371/journal.pgen.1002650
_version_ 1782233949613850624
author Tran, Phuoc T.
Shroff, Emelyn H.
Burns, Timothy F.
Thiyagarajan, Saravanan
Das, Sandhya T.
Zabuawala, Tahera
Chen, Joy
Cho, Yoon-Jae
Luong, Richard
Tamayo, Pablo
Salih, Tarek
Aziz, Khaled
Adam, Stacey J.
Vicent, Silvestre
Nielsen, Carsten H.
Withofs, Nadia
Sweet-Cordero, Alejandro
Gambhir, Sanjiv S.
Rudin, Charles M.
Felsher, Dean W.
author_facet Tran, Phuoc T.
Shroff, Emelyn H.
Burns, Timothy F.
Thiyagarajan, Saravanan
Das, Sandhya T.
Zabuawala, Tahera
Chen, Joy
Cho, Yoon-Jae
Luong, Richard
Tamayo, Pablo
Salih, Tarek
Aziz, Khaled
Adam, Stacey J.
Vicent, Silvestre
Nielsen, Carsten H.
Withofs, Nadia
Sweet-Cordero, Alejandro
Gambhir, Sanjiv S.
Rudin, Charles M.
Felsher, Dean W.
author_sort Tran, Phuoc T.
collection PubMed
description KRAS mutant lung cancers are generally refractory to chemotherapy as well targeted agents. To date, the identification of drugs to therapeutically inhibit K-RAS have been unsuccessful, suggesting that other approaches are required. We demonstrate in both a novel transgenic mutant Kras lung cancer mouse model and in human lung tumors that the inhibition of Twist1 restores a senescence program inducing the loss of a neoplastic phenotype. The Twist1 gene encodes for a transcription factor that is essential during embryogenesis. Twist1 has been suggested to play an important role during tumor progression. However, there is no in vivo evidence that Twist1 plays a role in autochthonous tumorigenesis. Through two novel transgenic mouse models, we show that Twist1 cooperates with Kras(G12D) to markedly accelerate lung tumorigenesis by abrogating cellular senescence programs and promoting the progression from benign adenomas to adenocarcinomas. Moreover, the suppression of Twist1 to physiological levels is sufficient to cause Kras mutant lung tumors to undergo senescence and lose their neoplastic features. Finally, we analyzed more than 500 human tumors to demonstrate that TWIST1 is frequently overexpressed in primary human lung tumors. The suppression of TWIST1 in human lung cancer cells also induced cellular senescence. Hence, TWIST1 is a critical regulator of cellular senescence programs, and the suppression of TWIST1 in human tumors may be an effective example of pro-senescence therapy.
format Online
Article
Text
id pubmed-3360067
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-33600672012-05-31 Twist1 Suppresses Senescence Programs and Thereby Accelerates and Maintains Mutant Kras-Induced Lung Tumorigenesis Tran, Phuoc T. Shroff, Emelyn H. Burns, Timothy F. Thiyagarajan, Saravanan Das, Sandhya T. Zabuawala, Tahera Chen, Joy Cho, Yoon-Jae Luong, Richard Tamayo, Pablo Salih, Tarek Aziz, Khaled Adam, Stacey J. Vicent, Silvestre Nielsen, Carsten H. Withofs, Nadia Sweet-Cordero, Alejandro Gambhir, Sanjiv S. Rudin, Charles M. Felsher, Dean W. PLoS Genet Research Article KRAS mutant lung cancers are generally refractory to chemotherapy as well targeted agents. To date, the identification of drugs to therapeutically inhibit K-RAS have been unsuccessful, suggesting that other approaches are required. We demonstrate in both a novel transgenic mutant Kras lung cancer mouse model and in human lung tumors that the inhibition of Twist1 restores a senescence program inducing the loss of a neoplastic phenotype. The Twist1 gene encodes for a transcription factor that is essential during embryogenesis. Twist1 has been suggested to play an important role during tumor progression. However, there is no in vivo evidence that Twist1 plays a role in autochthonous tumorigenesis. Through two novel transgenic mouse models, we show that Twist1 cooperates with Kras(G12D) to markedly accelerate lung tumorigenesis by abrogating cellular senescence programs and promoting the progression from benign adenomas to adenocarcinomas. Moreover, the suppression of Twist1 to physiological levels is sufficient to cause Kras mutant lung tumors to undergo senescence and lose their neoplastic features. Finally, we analyzed more than 500 human tumors to demonstrate that TWIST1 is frequently overexpressed in primary human lung tumors. The suppression of TWIST1 in human lung cancer cells also induced cellular senescence. Hence, TWIST1 is a critical regulator of cellular senescence programs, and the suppression of TWIST1 in human tumors may be an effective example of pro-senescence therapy. Public Library of Science 2012-05-24 /pmc/articles/PMC3360067/ /pubmed/22654667 http://dx.doi.org/10.1371/journal.pgen.1002650 Text en Tran et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Tran, Phuoc T.
Shroff, Emelyn H.
Burns, Timothy F.
Thiyagarajan, Saravanan
Das, Sandhya T.
Zabuawala, Tahera
Chen, Joy
Cho, Yoon-Jae
Luong, Richard
Tamayo, Pablo
Salih, Tarek
Aziz, Khaled
Adam, Stacey J.
Vicent, Silvestre
Nielsen, Carsten H.
Withofs, Nadia
Sweet-Cordero, Alejandro
Gambhir, Sanjiv S.
Rudin, Charles M.
Felsher, Dean W.
Twist1 Suppresses Senescence Programs and Thereby Accelerates and Maintains Mutant Kras-Induced Lung Tumorigenesis
title Twist1 Suppresses Senescence Programs and Thereby Accelerates and Maintains Mutant Kras-Induced Lung Tumorigenesis
title_full Twist1 Suppresses Senescence Programs and Thereby Accelerates and Maintains Mutant Kras-Induced Lung Tumorigenesis
title_fullStr Twist1 Suppresses Senescence Programs and Thereby Accelerates and Maintains Mutant Kras-Induced Lung Tumorigenesis
title_full_unstemmed Twist1 Suppresses Senescence Programs and Thereby Accelerates and Maintains Mutant Kras-Induced Lung Tumorigenesis
title_short Twist1 Suppresses Senescence Programs and Thereby Accelerates and Maintains Mutant Kras-Induced Lung Tumorigenesis
title_sort twist1 suppresses senescence programs and thereby accelerates and maintains mutant kras-induced lung tumorigenesis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3360067/
https://www.ncbi.nlm.nih.gov/pubmed/22654667
http://dx.doi.org/10.1371/journal.pgen.1002650
work_keys_str_mv AT tranphuoct twist1suppressessenescenceprogramsandtherebyacceleratesandmaintainsmutantkrasinducedlungtumorigenesis
AT shroffemelynh twist1suppressessenescenceprogramsandtherebyacceleratesandmaintainsmutantkrasinducedlungtumorigenesis
AT burnstimothyf twist1suppressessenescenceprogramsandtherebyacceleratesandmaintainsmutantkrasinducedlungtumorigenesis
AT thiyagarajansaravanan twist1suppressessenescenceprogramsandtherebyacceleratesandmaintainsmutantkrasinducedlungtumorigenesis
AT dassandhyat twist1suppressessenescenceprogramsandtherebyacceleratesandmaintainsmutantkrasinducedlungtumorigenesis
AT zabuawalatahera twist1suppressessenescenceprogramsandtherebyacceleratesandmaintainsmutantkrasinducedlungtumorigenesis
AT chenjoy twist1suppressessenescenceprogramsandtherebyacceleratesandmaintainsmutantkrasinducedlungtumorigenesis
AT choyoonjae twist1suppressessenescenceprogramsandtherebyacceleratesandmaintainsmutantkrasinducedlungtumorigenesis
AT luongrichard twist1suppressessenescenceprogramsandtherebyacceleratesandmaintainsmutantkrasinducedlungtumorigenesis
AT tamayopablo twist1suppressessenescenceprogramsandtherebyacceleratesandmaintainsmutantkrasinducedlungtumorigenesis
AT salihtarek twist1suppressessenescenceprogramsandtherebyacceleratesandmaintainsmutantkrasinducedlungtumorigenesis
AT azizkhaled twist1suppressessenescenceprogramsandtherebyacceleratesandmaintainsmutantkrasinducedlungtumorigenesis
AT adamstaceyj twist1suppressessenescenceprogramsandtherebyacceleratesandmaintainsmutantkrasinducedlungtumorigenesis
AT vicentsilvestre twist1suppressessenescenceprogramsandtherebyacceleratesandmaintainsmutantkrasinducedlungtumorigenesis
AT nielsencarstenh twist1suppressessenescenceprogramsandtherebyacceleratesandmaintainsmutantkrasinducedlungtumorigenesis
AT withofsnadia twist1suppressessenescenceprogramsandtherebyacceleratesandmaintainsmutantkrasinducedlungtumorigenesis
AT sweetcorderoalejandro twist1suppressessenescenceprogramsandtherebyacceleratesandmaintainsmutantkrasinducedlungtumorigenesis
AT gambhirsanjivs twist1suppressessenescenceprogramsandtherebyacceleratesandmaintainsmutantkrasinducedlungtumorigenesis
AT rudincharlesm twist1suppressessenescenceprogramsandtherebyacceleratesandmaintainsmutantkrasinducedlungtumorigenesis
AT felsherdeanw twist1suppressessenescenceprogramsandtherebyacceleratesandmaintainsmutantkrasinducedlungtumorigenesis