The Oncogenic FOXL2 C134W Mutation Is a Key Driver of Granulosa Cell Tumors

The Oncogenic FOXL2 C134W Mutation Is a Key Driver of Granulosa Cell Tumors

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Molecular Cell Biology|
January 18 2023

Elena Llano

;

1Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biologıía Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain.

2Departamento de Fisiología, Universidad de Salamanca, Salamanca, Spain.

*Corresponding Authors: Alberto M. Pendas, Molecular Mechanisms Program, Centro de Investigacion del Cáncer, Universidad de Salamanca-CSIC, Campus Miguel de Unamuno, Salamanca 37007, Spain. E-mail: amp@usal.es; Elena Llano, Departamento Fisiología, Universidad de Salamanca, Salamanca, Spain. E-mail: ellano@usal.es; and Reiner A. Veitia, Institut Jacques Monod, Paris Cedex 13, France. E-mail: reiner.veitia@ijm.fr

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Anne Laure Todeschini

;

3Université Paris Cité, CNRS, Institut Jacques Monod, Paris, France.

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Natalia Felipe-Medina

;

1Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biologıía Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain.

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María D. Corte-Torres

;

4Instituto de Investigación Sanitaria de Asturias, Hospital Universitario del Principado de Asturias, Oviedo, Spain.

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Yazmine B. Condezo

;

1Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biologıía Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain.

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Manuel Sanchez-Martin

;

5Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain.

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Sara López-Tamargo

;

6Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.

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Aurora Astudillo

;

4Instituto de Investigación Sanitaria de Asturias, Hospital Universitario del Principado de Asturias, Oviedo, Spain.

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Xose S. Puente

;

7Departamento de Bioquímica, Universidad de Oviedo, Oviedo, Spain.

8Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.

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Alberto M. Pendas

;

1Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biologıía Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain.

*Corresponding Authors: Alberto M. Pendas, Molecular Mechanisms Program, Centro de Investigacion del Cáncer, Universidad de Salamanca-CSIC, Campus Miguel de Unamuno, Salamanca 37007, Spain. E-mail: amp@usal.es; Elena Llano, Departamento Fisiología, Universidad de Salamanca, Salamanca, Spain. E-mail: ellano@usal.es; and Reiner A. Veitia, Institut Jacques Monod, Paris Cedex 13, France. E-mail: reiner.veitia@ijm.fr

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Reiner A. Veitia

3Université Paris Cité, CNRS, Institut Jacques Monod, Paris, France.

9Université Paris Saclay, Paris, France.

10Institut de Biologie François Jacob, CEA, Fontenay-aux-Roses, Paris, France.

*Corresponding Authors: Alberto M. Pendas, Molecular Mechanisms Program, Centro de Investigacion del Cáncer, Universidad de Salamanca-CSIC, Campus Miguel de Unamuno, Salamanca 37007, Spain. E-mail: amp@usal.es; Elena Llano, Departamento Fisiología, Universidad de Salamanca, Salamanca, Spain. E-mail: ellano@usal.es; and Reiner A. Veitia, Institut Jacques Monod, Paris Cedex 13, France. E-mail: reiner.veitia@ijm.fr

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Crossmark: Check for Updates

*Corresponding Authors: Alberto M. Pendas, Molecular Mechanisms Program, Centro de Investigacion del Cáncer, Universidad de Salamanca-CSIC, Campus Miguel de Unamuno, Salamanca 37007, Spain. E-mail: amp@usal.es; Elena Llano, Departamento Fisiología, Universidad de Salamanca, Salamanca, Spain. E-mail: ellano@usal.es; and Reiner A. Veitia, Institut Jacques Monod, Paris Cedex 13, France. E-mail: reiner.veitia@ijm.fr

Cancer Res 2023;83:239–50

Received:
June 09 2022

Revision Received:
October 24 2022

Accepted:
November 15 2022

Online ISSN: 1538-7445

Print ISSN: 0008-5472

Funding

Funding Group:

  • Award Group:

    • Funder(s):

       Ministerio de Ciencia e Innovación (MICINN)

    • Award Id(s):

      PID2020-120326RB-I00

    • Principal Award Recipient(s):
  • Award Group:

    • Funder(s):

       Junta de Castilla y León (JCYL)

    • Award Id(s):

      CSI239P18 and CSI148P20

    • Principal Award Recipient(s):
  • Award Group:

    • Funder(s):

       Commissariat à l’Énergie Atomique et aux Énergies Alternatives (CEA)

    • Principal Award Recipient(s):
  • Award Group:

    • Funder(s):

       Ministerio de Ciencia e Innovación (MICINN)

    • Award Id(s):

      PID2020-117185RB-I00

    • Principal Award Recipient(s):
  • Award Group:

    • Funder(s):

       Junta de Castilla y León (JCYL)

    • Award Id(s):

      CLC&#x2013

      ,

      2017&#x2013

      ,

      01

    • Principal Award Recipient(s):

©2022 American Association for Cancer Research

2022

American Association for Cancer Research

Cancer Res (2023) 83 (2): 239–250.


Article history

Revision Received:

October 24 2022

Accepted:

November 15 2022

Abstract

Adult-type granulosa cell tumors (AGCT) are the most common type of malignant ovarian sex cord–stromal tumors. Most AGCTs carry the somatic variant c.402C>G (p.C134W) affecting the transcription factor FOXL2. Germline dominant variants in FOXL2 are responsible for blepharophimosis syndrome, which is characterized by underdevelopment of the eyelid. In this work, we generated a mouse model harboring the C134W variant of FOXL2 to evaluate in vivo the poorly understood oncogenic role of FOXL2. The mutation was dominant regarding eyelid hypoplasia, reminiscent of blepharophimosis syndrome. Interestingly, Foxl2+/C134W female mice had reduced fertility and developed AGCTs through a progression from abnormal ovaries with aberrant granulosa cells to ovaries with stromal hyperplasia and atypia and on to tumors in adut mice. The genes dysregulated in mouse AGCTs exhibited the hallmarks of cancer and were consistent with a gain-of-function of the mutated allele affecting TGFβ signaling. A comparison of these data with previous results on human AGCTs indicated similar deregulated pathways. Finally, a mutational analysis of mouse AGCT transcriptomic data suggested the absence of additional driver mutations apart from FOXL2-C134W. These results provide a clear in vivo example in which a single mutational hit triggers tumor development associated with profound transcriptomic alterations.

Significance:

A newly generated mouse model carrying a FOXL2 mutation characteristic of adult-type granulosa cell tumors shows that FOXL2 C134W shifts the transcriptome towards a signature of granulosa cell cancer and drives tumorigenesis.

©2022 American Association for Cancer Research

2022

American Association for Cancer Research

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