The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas

Eva Hernando; Elizabeth Charytonowicz; Maria E. Dudas; Silvia Menendez; Igor Matushansky; Joslyn Mills; Nicholas D. Socci; Nille Behrendt; Li Ma; Robert G. Maki; Pier Paolo Pandolfi; Carlos Cordon-Cardo

doi:10.1038/nm1560

The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas

Eva Hernando
, Elizabeth Charytonowicz
, Maria E. Dudas
, Silvia Menendez
, Igor Matushansky
, Joslyn Mills
, Nicholas D. Socci
, Nille Behrendt
, Li Ma
, Robert G. Maki
, Pier Paolo Pandolfi^*
, Carlos Cordon-Cardo

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

Abstract

We analyzed the PI3K-AKT signaling cascade in a cohort of sarcomas and found a marked induction of insulin receptor substrate-2 (IRS2) and phosphorylated AKT and a concomitant upregulation of downstream effectors in most leiomyosarcomas. To determine the role of aberrant PI3K-AKT signaling in leiomyosarcoma pathogenesis, we genetically inactivated Pten in the smooth muscle cell lineage by cross-breeding Pten^loxP/loxP mice with Tagln-cre mice. Mice carrying homozygous deletion of Pten alleles developed widespread smooth muscle cell hyperplasia and abdominal leiomyosarcomas, with a very rapid onset and elevated incidence (∼80%) compared to other animal models. Constitutive mTOR activation was restricted to the leiomyosarcomas, revealing the requirement for additional molecular events besides Pten loss. The rapamycin derivative everolimus substantially decelerated tumor growth on Tagln-cre/Pten^loxP/loxP mice and prolonged their lifespan. Our data show a new and critical role for the AKT-mTOR pathway in smooth muscle transformation and leiomyosarcoma genesis, and support treatment of selected sarcomas by the targeting of this pathway with new compounds or combinations of these with conventional chemotherapy agents.

Original language	English
Pages (from-to)	748-753
Number of pages	6
Journal	Nature Medicine
Volume	13
Issue number	6
DOIs	https://doi.org/10.1038/nm1560
Publication status	Published - 1 Jun 2007

Funding

We thank C. Matei, C. Le and M. Lupu for help with the MRI analysis; W. Golden, T. Matos and M.S. Jiao for technical assistance; and E. Diaz-Rodriguez, R. Sotillo and members of the C.C.-C. and P.P.P. laboratories (T.-H. Shen, M. Drobnjak, A. Alimonti, L. Trotman) for discussion, editorial advice and critical reading of the manuscript. We thank R. Parsons (Columbia University) for the IRS2 antibody; A.J. Levine (University of Medicine and Dentistry of New Jersey (UMDNJ)) for the MDM2 antibody; and S.W. Lowe (Cold Spring Harbor Laboratory (CSHL)) for the PML antibody. This work was partially supported by philantropic funds from the R.O. Perelman foundation. C.C.-C. and P.P.P. are supported by grants from the US National Institutes of Health (NIH/NCI PO1 CA47179).

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10.1038/nm1560

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title = "The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas",

abstract = "We analyzed the PI3K-AKT signaling cascade in a cohort of sarcomas and found a marked induction of insulin receptor substrate-2 (IRS2) and phosphorylated AKT and a concomitant upregulation of downstream effectors in most leiomyosarcomas. To determine the role of aberrant PI3K-AKT signaling in leiomyosarcoma pathogenesis, we genetically inactivated Pten in the smooth muscle cell lineage by cross-breeding PtenloxP/loxP mice with Tagln-cre mice. Mice carrying homozygous deletion of Pten alleles developed widespread smooth muscle cell hyperplasia and abdominal leiomyosarcomas, with a very rapid onset and elevated incidence (∼80\%) compared to other animal models. Constitutive mTOR activation was restricted to the leiomyosarcomas, revealing the requirement for additional molecular events besides Pten loss. The rapamycin derivative everolimus substantially decelerated tumor growth on Tagln-cre/PtenloxP/loxP mice and prolonged their lifespan. Our data show a new and critical role for the AKT-mTOR pathway in smooth muscle transformation and leiomyosarcoma genesis, and support treatment of selected sarcomas by the targeting of this pathway with new compounds or combinations of these with conventional chemotherapy agents.",

author = "Eva Hernando and Elizabeth Charytonowicz and Dudas, \{Maria E.\} and Silvia Menendez and Igor Matushansky and Joslyn Mills and Socci, \{Nicholas D.\} and Nille Behrendt and Li Ma and Maki, \{Robert G.\} and Pandolfi, \{Pier Paolo\} and Carlos Cordon-Cardo",

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AU - Matushansky, Igor

AU - Mills, Joslyn

AU - Socci, Nicholas D.

AU - Behrendt, Nille

AU - Ma, Li

AU - Maki, Robert G.

AU - Pandolfi, Pier Paolo

AU - Cordon-Cardo, Carlos

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AB - We analyzed the PI3K-AKT signaling cascade in a cohort of sarcomas and found a marked induction of insulin receptor substrate-2 (IRS2) and phosphorylated AKT and a concomitant upregulation of downstream effectors in most leiomyosarcomas. To determine the role of aberrant PI3K-AKT signaling in leiomyosarcoma pathogenesis, we genetically inactivated Pten in the smooth muscle cell lineage by cross-breeding PtenloxP/loxP mice with Tagln-cre mice. Mice carrying homozygous deletion of Pten alleles developed widespread smooth muscle cell hyperplasia and abdominal leiomyosarcomas, with a very rapid onset and elevated incidence (∼80%) compared to other animal models. Constitutive mTOR activation was restricted to the leiomyosarcomas, revealing the requirement for additional molecular events besides Pten loss. The rapamycin derivative everolimus substantially decelerated tumor growth on Tagln-cre/PtenloxP/loxP mice and prolonged their lifespan. Our data show a new and critical role for the AKT-mTOR pathway in smooth muscle transformation and leiomyosarcoma genesis, and support treatment of selected sarcomas by the targeting of this pathway with new compounds or combinations of these with conventional chemotherapy agents.

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ER -

The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas

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