Twist1 suppresses senescence programs and thereby accelerates and maintains mutant Kras-induced lung tumorigenesis

Phuoc T Tran; Emelyn H Shroff; Timothy F Burns; Saravanan Thiyagarajan; Sandhya T Das; Tahera Zabuawala; Joy Chen; Yoon-Jae Cho; Richard Luong; Pablo Tamayo; Tarek Salih; Khaled Aziz; Stacey J Adam; Silvestre Vicent; Carsten Haagen Nielsen; Nadia Withofs; Alejandro Sweet-Cordero; Sanjiv S Gambhir; Charles M Rudin; Dean W Felsher

doi:10.1371/journal.pgen.1002650

Twist1 suppresses senescence programs and thereby accelerates and maintains mutant Kras-induced lung tumorigenesis

Phuoc T Tran, Emelyn H Shroff, Timothy F Burns, Saravanan Thiyagarajan, Sandhya T Das, Tahera Zabuawala, Joy Chen, Yoon-Jae Cho, Richard Luong, Pablo Tamayo, Tarek Salih, Khaled Aziz, Stacey J Adam, Silvestre Vicent, Carsten Haagen Nielsen, Nadia Withofs, Alejandro Sweet-Cordero, Sanjiv S Gambhir, Charles M Rudin, Dean W Felsher

Department of Biomedical Sciences

76 Citations (Scopus)

Abstract

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.

Original language	English
Journal	P L o S Genetics (Online)
Volume	8
Issue number	5
Pages (from-to)	1-10
Number of pages	11
ISSN	1553-7404
DOIs	https://doi.org/10.1371/journal.pgen.1002650
Publication status	Published - 24 May 2012

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Tran, P. T., Shroff, E. H., Burns, T. F., Thiyagarajan, S., Das, S. T., Zabuawala, T., Chen, J., Cho, Y.-J., Luong, R., Tamayo, P., Salih, T., Aziz, K., Adam, S. J., Vicent, S., Nielsen, C. H., Withofs, N., Sweet-Cordero, A., Gambhir, S. S., Rudin, C. M., & Felsher, D. W. (2012). Twist1 suppresses senescence programs and thereby accelerates and maintains mutant Kras-induced lung tumorigenesis. P L o S Genetics (Online), 8(5), 1-10. https://doi.org/10.1371/journal.pgen.1002650

Tran, PT, Shroff, EH, Burns, TF, Thiyagarajan, S, Das, ST, Zabuawala, T, Chen, J, Cho, Y-J, Luong, R, Tamayo, P, Salih, T, Aziz, K, Adam, SJ, Vicent, S, Nielsen, CH, Withofs, N, Sweet-Cordero, A, Gambhir, SS, Rudin, CM & Felsher, DW 2012, 'Twist1 suppresses senescence programs and thereby accelerates and maintains mutant Kras-induced lung tumorigenesis', P L o S Genetics (Online), vol. 8, no. 5, pp. 1-10. https://doi.org/10.1371/journal.pgen.1002650

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abstract = "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.",

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AU - Das, Sandhya T

AU - Zabuawala, Tahera

AU - Chen, Joy

AU - Cho, Yoon-Jae

AU - Luong, Richard

AU - Tamayo, Pablo

AU - Salih, Tarek

AU - Aziz, Khaled

AU - Adam, Stacey J

AU - Vicent, Silvestre

AU - Nielsen, Carsten Haagen

AU - Withofs, Nadia

AU - Sweet-Cordero, Alejandro

AU - Gambhir, Sanjiv S

AU - Rudin, Charles M

AU - Felsher, Dean W

PY - 2012/5/24

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N2 - 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.

AB - 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.

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JF - P L o S Genetics (Online)

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ER -

Twist1 suppresses senescence programs and thereby accelerates and maintains mutant Kras-induced lung tumorigenesis

Abstract

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