Thyrocyte-specific inactivation of p53 and Pten results in anaplastic thyroid carcinomas faithfully recapitulating human tumors

Valeria G. Antico Arciuch, Marika A. Russo, Mariavittoria Dima, Kristy S. Kang, Florence Dasrath, Xiao Hui Liao, Samuel Refetoff, Cristina Montagna, Antonio Di Cristofano

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer, and often derives from pre-existing well-differentiated tumors. Despite a relatively low prevalence, it accounts for a disproportionate number of thyroid cancer-related deaths, due to its resistance to any therapeutic approach. Here we describe the first mouse model of ATC, obtained by combining in the mouse thyroid follicular cells two molecular hallmarks of human ATC: activation of PI3K (via Pten deletion) and inactivation of p53. By 9 months of age, over 75% of the compound mutant mice develop aggressive, undifferentiated thyroid tumors that evolve from pre-existing follicular hyperplasia and carcinoma. These tumors display all the features of their human counterpart, including pleomorphism, epithelial-mesenchymal transition, aneuploidy, local invasion, and distant metastases. Expression profiling of the murine ATCs reveals a significant overlap with genes found deregulated in human ATC, including genes involved in mitosis control. Furthermore, similar to the human tumors, [Pten, p53]thyr-/-tumors and cells are highly glycolytic and remarkably sensitive to glycolysis inhibitors, which synergize with standard chemotherapy. Taken together, our results show that combined PI3K activation and p53 loss faithfully reproduce the development of thyroid anaplastic carcinomas, and provide a compelling rationale for targeting glycolysis to increase chemotherapy response in ATC patients.

Original languageEnglish (US)
Pages (from-to)1109-1126
Number of pages18
JournalOncotarget
Volume2
Issue number12
StatePublished - Dec 2011

Fingerprint

Neoplasms
Glycolysis
Phosphatidylinositol 3-Kinases
Thyroid Neoplasms
Drug Therapy
Epithelial-Mesenchymal Transition
Aneuploidy
Mitosis
Genes
Hyperplasia
Anaplastic Thyroid Carcinoma
Thyroid Epithelial Cells
Thyroid Gland
Neoplasm Metastasis
Carcinoma
Therapeutics

Keywords

  • Anaplastic
  • Glycolysis
  • Mouse model
  • P53
  • PI3K
  • Pten
  • Thyroid cancer

ASJC Scopus subject areas

  • Oncology

Cite this

Antico Arciuch, V. G., Russo, M. A., Dima, M., Kang, K. S., Dasrath, F., Liao, X. H., ... Di Cristofano, A. (2011). Thyrocyte-specific inactivation of p53 and Pten results in anaplastic thyroid carcinomas faithfully recapitulating human tumors. Oncotarget, 2(12), 1109-1126.

Thyrocyte-specific inactivation of p53 and Pten results in anaplastic thyroid carcinomas faithfully recapitulating human tumors. / Antico Arciuch, Valeria G.; Russo, Marika A.; Dima, Mariavittoria; Kang, Kristy S.; Dasrath, Florence; Liao, Xiao Hui; Refetoff, Samuel; Montagna, Cristina; Di Cristofano, Antonio.

In: Oncotarget, Vol. 2, No. 12, 12.2011, p. 1109-1126.

Research output: Contribution to journalArticle

Antico Arciuch, VG, Russo, MA, Dima, M, Kang, KS, Dasrath, F, Liao, XH, Refetoff, S, Montagna, C & Di Cristofano, A 2011, 'Thyrocyte-specific inactivation of p53 and Pten results in anaplastic thyroid carcinomas faithfully recapitulating human tumors', Oncotarget, vol. 2, no. 12, pp. 1109-1126.
Antico Arciuch VG, Russo MA, Dima M, Kang KS, Dasrath F, Liao XH et al. Thyrocyte-specific inactivation of p53 and Pten results in anaplastic thyroid carcinomas faithfully recapitulating human tumors. Oncotarget. 2011 Dec;2(12):1109-1126.
Antico Arciuch, Valeria G. ; Russo, Marika A. ; Dima, Mariavittoria ; Kang, Kristy S. ; Dasrath, Florence ; Liao, Xiao Hui ; Refetoff, Samuel ; Montagna, Cristina ; Di Cristofano, Antonio. / Thyrocyte-specific inactivation of p53 and Pten results in anaplastic thyroid carcinomas faithfully recapitulating human tumors. In: Oncotarget. 2011 ; Vol. 2, No. 12. pp. 1109-1126.
@article{6e16aaac157b46ac93938f719f77a6d4,
title = "Thyrocyte-specific inactivation of p53 and Pten results in anaplastic thyroid carcinomas faithfully recapitulating human tumors",
abstract = "Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer, and often derives from pre-existing well-differentiated tumors. Despite a relatively low prevalence, it accounts for a disproportionate number of thyroid cancer-related deaths, due to its resistance to any therapeutic approach. Here we describe the first mouse model of ATC, obtained by combining in the mouse thyroid follicular cells two molecular hallmarks of human ATC: activation of PI3K (via Pten deletion) and inactivation of p53. By 9 months of age, over 75{\%} of the compound mutant mice develop aggressive, undifferentiated thyroid tumors that evolve from pre-existing follicular hyperplasia and carcinoma. These tumors display all the features of their human counterpart, including pleomorphism, epithelial-mesenchymal transition, aneuploidy, local invasion, and distant metastases. Expression profiling of the murine ATCs reveals a significant overlap with genes found deregulated in human ATC, including genes involved in mitosis control. Furthermore, similar to the human tumors, [Pten, p53]thyr-/-tumors and cells are highly glycolytic and remarkably sensitive to glycolysis inhibitors, which synergize with standard chemotherapy. Taken together, our results show that combined PI3K activation and p53 loss faithfully reproduce the development of thyroid anaplastic carcinomas, and provide a compelling rationale for targeting glycolysis to increase chemotherapy response in ATC patients.",
keywords = "Anaplastic, Glycolysis, Mouse model, P53, PI3K, Pten, Thyroid cancer",
author = "{Antico Arciuch}, {Valeria G.} and Russo, {Marika A.} and Mariavittoria Dima and Kang, {Kristy S.} and Florence Dasrath and Liao, {Xiao Hui} and Samuel Refetoff and Cristina Montagna and {Di Cristofano}, Antonio",
year = "2011",
month = "12",
language = "English (US)",
volume = "2",
pages = "1109--1126",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "12",

}

TY - JOUR

T1 - Thyrocyte-specific inactivation of p53 and Pten results in anaplastic thyroid carcinomas faithfully recapitulating human tumors

AU - Antico Arciuch, Valeria G.

AU - Russo, Marika A.

AU - Dima, Mariavittoria

AU - Kang, Kristy S.

AU - Dasrath, Florence

AU - Liao, Xiao Hui

AU - Refetoff, Samuel

AU - Montagna, Cristina

AU - Di Cristofano, Antonio

PY - 2011/12

Y1 - 2011/12

N2 - Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer, and often derives from pre-existing well-differentiated tumors. Despite a relatively low prevalence, it accounts for a disproportionate number of thyroid cancer-related deaths, due to its resistance to any therapeutic approach. Here we describe the first mouse model of ATC, obtained by combining in the mouse thyroid follicular cells two molecular hallmarks of human ATC: activation of PI3K (via Pten deletion) and inactivation of p53. By 9 months of age, over 75% of the compound mutant mice develop aggressive, undifferentiated thyroid tumors that evolve from pre-existing follicular hyperplasia and carcinoma. These tumors display all the features of their human counterpart, including pleomorphism, epithelial-mesenchymal transition, aneuploidy, local invasion, and distant metastases. Expression profiling of the murine ATCs reveals a significant overlap with genes found deregulated in human ATC, including genes involved in mitosis control. Furthermore, similar to the human tumors, [Pten, p53]thyr-/-tumors and cells are highly glycolytic and remarkably sensitive to glycolysis inhibitors, which synergize with standard chemotherapy. Taken together, our results show that combined PI3K activation and p53 loss faithfully reproduce the development of thyroid anaplastic carcinomas, and provide a compelling rationale for targeting glycolysis to increase chemotherapy response in ATC patients.

AB - Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer, and often derives from pre-existing well-differentiated tumors. Despite a relatively low prevalence, it accounts for a disproportionate number of thyroid cancer-related deaths, due to its resistance to any therapeutic approach. Here we describe the first mouse model of ATC, obtained by combining in the mouse thyroid follicular cells two molecular hallmarks of human ATC: activation of PI3K (via Pten deletion) and inactivation of p53. By 9 months of age, over 75% of the compound mutant mice develop aggressive, undifferentiated thyroid tumors that evolve from pre-existing follicular hyperplasia and carcinoma. These tumors display all the features of their human counterpart, including pleomorphism, epithelial-mesenchymal transition, aneuploidy, local invasion, and distant metastases. Expression profiling of the murine ATCs reveals a significant overlap with genes found deregulated in human ATC, including genes involved in mitosis control. Furthermore, similar to the human tumors, [Pten, p53]thyr-/-tumors and cells are highly glycolytic and remarkably sensitive to glycolysis inhibitors, which synergize with standard chemotherapy. Taken together, our results show that combined PI3K activation and p53 loss faithfully reproduce the development of thyroid anaplastic carcinomas, and provide a compelling rationale for targeting glycolysis to increase chemotherapy response in ATC patients.

KW - Anaplastic

KW - Glycolysis

KW - Mouse model

KW - P53

KW - PI3K

KW - Pten

KW - Thyroid cancer

UR - http://www.scopus.com/inward/record.url?scp=84865273469&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84865273469&partnerID=8YFLogxK

M3 - Article

VL - 2

SP - 1109

EP - 1126

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 12

ER -