An autocrine ActivinB mechanism drives TGFβ/Activin signaling in Group 3 medulloblastoma

Morgane Morabito; Magalie Larcher; Florence Mg Cavalli; Chloé Foray; Antoine Forget; Liliana Mirabal-Ortega; Mamy Andrianteranagna; Sabine Druillennec; Alexandra Garancher; Julien Masliah-Planchon; Sophie Leboucher; Abel Debalkew; Alessandro Raso; Olivier Delattre; Stéphanie Puget; François Doz; Michael D Taylor; Olivier Ayrault; Franck Bourdeaut; Alain Eychène; Celio Pouponnot

doi:10.15252/emmm.201809830

An autocrine ActivinB mechanism drives TGFβ/Activin signaling in Group 3 medulloblastoma

EMBO Mol Med. 2019 Aug;11(8):e9830. doi: 10.15252/emmm.201809830. Epub 2019 Jul 22.

Authors

Morgane Morabito^{1

2

3

4

5}, Magalie Larcher^{1

2

3

4

5}, Florence Mg Cavalli^{6

7}, Chloé Foray^{1

2

3

4

5}, Antoine Forget^{1

2

3

4

5}, Liliana Mirabal-Ortega^{1

2

3

4

5}, Mamy Andrianteranagna^{5

8

9

10

11

12

13}, Sabine Druillennec^{1

2

3

4

5}, Alexandra Garancher^{1

2

3

4

5}, Julien Masliah-Planchon^{5

8

9

11}, Sophie Leboucher^{1

4}, Abel Debalkew^{6

7}, Alessandro Raso¹⁴, Olivier Delattre^{5

8

9

11}, Stéphanie Puget^{15

16}, François Doz^{8

11

15}, Michael D Taylor^{6

7

17

18}, Olivier Ayrault^{1

2

3

4

5}, Franck Bourdeaut^{5

8

9

10

11}, Alain Eychène^{1

2

3

4

5}, Celio Pouponnot^{1

2

3

4

5}

Affiliations

¹ Institut Curie, Orsay, France.
² INSERM U1021, Centre Universitaire, Orsay, France.
³ CNRS UMR 3347, Centre Universitaire, Orsay, France.
⁴ University Paris Sud - Paris-Saclay, Orsay, France.
⁵ PSL Research University, Paris, France.
⁶ The Arthur and Sonia Labatt Brain Tumour Research Center, The Hospital for Sick Children, Toronto, ON, Canada.
⁷ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
⁸ Institut Curie, Paris, France.
⁹ INSERM U830, Paris, France.
¹⁰ Translational Research in Pediatric Oncology, Institut Curie SiRIC, Paris, France.
¹¹ SIREDO Center (Care, innovation, Research in pediatric, adolescent and young adult oncology), Institut Curie, Paris, France.
¹² INSERM, U900, Paris, France.
¹³ MINES ParisTech, CBIO-Centre for Computational Biology, Paris, France.
¹⁴ Department of Patology, ASL 3 Genovese, SC Laboratorio d'Analisi, Genova, Italy.
¹⁵ Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
¹⁶ Département Neurochirurgie Pédiatrique, AP-HP, Hôpital Necker-Enfants Malades, Paris, France.
¹⁷ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹⁸ Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada.

Abstract

Medulloblastoma (MB) is a pediatric tumor of the cerebellum divided into four groups. Group 3 is of bad prognosis and remains poorly characterized. While the current treatment involving surgery, radiotherapy, and chemotherapy often fails, no alternative therapy is yet available. Few recurrent genomic alterations that can be therapeutically targeted have been identified. Amplifications of receptors of the TGFβ/Activin pathway occur at very low frequency in Group 3 MB. However, neither their functional relevance nor activation of the downstream signaling pathway has been studied. We showed that this pathway is activated in Group 3 MB with some samples showing a very strong activation. Beside genetic alterations, we demonstrated that an ActivinB autocrine stimulation is responsible for pathway activation in a subset of Group 3 MB characterized by high PMEPA1 levels. Importantly, Galunisertib, a kinase inhibitor of the cognate receptors currently tested in clinical trials for Glioblastoma patients, showed efficacy on orthotopically grafted MB-PDX. Our data demonstrate that the TGFβ/Activin pathway is active in a subset of Group 3 MB and can be therapeutically targeted.

Keywords: Smad2; Smad3; TGFbeta; activin; medulloblastoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Apoptosis
Autocrine Communication*
Cell Line, Tumor
Cell Proliferation
Cerebellar Neoplasms / drug therapy
Cerebellar Neoplasms / genetics
Cerebellar Neoplasms / metabolism*
Cerebellar Neoplasms / pathology
Female
Gene Expression Regulation, Neoplastic
Humans
Inhibin-beta Subunits / genetics
Inhibin-beta Subunits / metabolism*
Medulloblastoma / drug therapy
Medulloblastoma / genetics
Medulloblastoma / metabolism*
Medulloblastoma / pathology
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mice, Nude
Phosphorylation
Pyrazoles / pharmacology
Quinolines / pharmacology
Signal Transduction
Smad2 Protein / metabolism
Smad3 Protein / metabolism
Transforming Growth Factor beta / genetics
Transforming Growth Factor beta / metabolism*
Transforming Growth Factor beta1 / genetics
Transforming Growth Factor beta1 / metabolism*
Transforming Growth Factor beta3 / genetics
Transforming Growth Factor beta3 / metabolism*
Tumor Burden
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
INHBB protein, human
Membrane Proteins
PMEPA1 protein, human
Pyrazoles
Quinolines
SMAD2 protein, human
SMAD3 protein, human
Smad2 Protein
Smad3 Protein
TGFB1 protein, human
TGFB3 protein, human
Transforming Growth Factor beta
Transforming Growth Factor beta1
Transforming Growth Factor beta3
LY-2157299
Inhibin-beta Subunits

Associated data

GEO/GSE85218

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding