TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling

Paloma Bragado; Yeriel Estrada; Falguni Parikh; Sarah Krause; Carla Capobianco; Hernan G. Farina; Denis M. Schewe; Julio A. Aguirre-Ghiso

doi:10.1038/ncb2861

TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling

Paloma Bragado, Yeriel Estrada, Falguni Parikh, Sarah Krause, Carla Capobianco, Hernan G. Farina, Denis M. Schewe, Julio A. Aguirre-Ghiso

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

365 Scopus citations

Abstract

In patients, non-proliferative disseminated tumour cells (DTCs) can persist in the bone marrow (BM) while other organs (such as lung) present growing metastasis. This suggested that the BM might be a metastasis 'restrictive soil' by encoding dormancy-inducing cues in DTCs. Here we show in a head and neck squamous cell carcinoma (HNSCC) model that strong and specific transforming growth factor-β2 (TGF-β2) signalling in the BM activates the MAPK p38α/β, inducing an (ERK/p38) low signalling ratio. This results in induction of DEC2/SHARP1 and p27, downregulation of cyclin-dependent kinase 4 (CDK4) and dormancy of malignant DTCs. TGF-β2-induced dormancy required TGF-β receptor-I (TGF-β-RI), TGF-β-RIII and SMAD1/5 activation to induce p27. In lungs, a metastasis 'permissive soil' with low TGF-β2 levels, DTC dormancy was short-lived and followed by metastatic growth. Importantly, systemic inhibition of TGF-β-RI or p38α/β activities awakened dormant DTCs, fuelling multi-organ metastasis. Our work reveals a 'seed and soil' mechanism where TGF-β2 and TGF-β-RIII signalling through p38α/β regulates DTC dormancy and defines restrictive (BM) and permissive (lung) microenvironments for HNSCC metastasis.

Original language	English
Pages (from-to)	1351-1361
Number of pages	11
Journal	Nature Cell Biology
Volume	15
Issue number	11
DOIs	https://doi.org/10.1038/ncb2861
State	Published - Nov 2013

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@article{f8b14ccefcda4de3bc20e8eb86f5e327,

title = "TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling",

abstract = "In patients, non-proliferative disseminated tumour cells (DTCs) can persist in the bone marrow (BM) while other organs (such as lung) present growing metastasis. This suggested that the BM might be a metastasis 'restrictive soil' by encoding dormancy-inducing cues in DTCs. Here we show in a head and neck squamous cell carcinoma (HNSCC) model that strong and specific transforming growth factor-β2 (TGF-β2) signalling in the BM activates the MAPK p38α/β, inducing an (ERK/p38) low signalling ratio. This results in induction of DEC2/SHARP1 and p27, downregulation of cyclin-dependent kinase 4 (CDK4) and dormancy of malignant DTCs. TGF-β2-induced dormancy required TGF-β receptor-I (TGF-β-RI), TGF-β-RIII and SMAD1/5 activation to induce p27. In lungs, a metastasis 'permissive soil' with low TGF-β2 levels, DTC dormancy was short-lived and followed by metastatic growth. Importantly, systemic inhibition of TGF-β-RI or p38α/β activities awakened dormant DTCs, fuelling multi-organ metastasis. Our work reveals a 'seed and soil' mechanism where TGF-β2 and TGF-β-RIII signalling through p38α/β regulates DTC dormancy and defines restrictive (BM) and permissive (lung) microenvironments for HNSCC metastasis.",

author = "Paloma Bragado and Yeriel Estrada and Falguni Parikh and Sarah Krause and Carla Capobianco and Farina, {Hernan G.} and Schewe, {Denis M.} and Aguirre-Ghiso, {Julio A.}",

note = "Funding Information: Grant support: Samuel Waxman Cancer Research Foundation Tumour Dormancy Program, NCI CA109182 and CA163131, NIEHS (ES017146) and NYSTEM grants to J.A.A-G; Mildred-Scheel postdoctoral grant by the Deutsche Krebshilfe and Max-Eder Junior Research Grant by the Deutsche Krebshilfe e. V. to D.M.S. C.C. is a research fellow and H.F. is an Investigator of CONICET—Argentina. This work was also supported by CONICET and UNQ grants to H.G.F.",

year = "2013",

month = nov,

doi = "10.1038/ncb2861",

language = "English",

volume = "15",

pages = "1351--1361",

journal = "Nature Cell Biology",

issn = "1465-7392",

publisher = "Nature Publishing Group",

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T1 - TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling

AU - Bragado, Paloma

AU - Estrada, Yeriel

AU - Parikh, Falguni

AU - Krause, Sarah

AU - Capobianco, Carla

AU - Farina, Hernan G.

AU - Schewe, Denis M.

AU - Aguirre-Ghiso, Julio A.

N1 - Funding Information: Grant support: Samuel Waxman Cancer Research Foundation Tumour Dormancy Program, NCI CA109182 and CA163131, NIEHS (ES017146) and NYSTEM grants to J.A.A-G; Mildred-Scheel postdoctoral grant by the Deutsche Krebshilfe and Max-Eder Junior Research Grant by the Deutsche Krebshilfe e. V. to D.M.S. C.C. is a research fellow and H.F. is an Investigator of CONICET—Argentina. This work was also supported by CONICET and UNQ grants to H.G.F.

PY - 2013/11

Y1 - 2013/11

N2 - In patients, non-proliferative disseminated tumour cells (DTCs) can persist in the bone marrow (BM) while other organs (such as lung) present growing metastasis. This suggested that the BM might be a metastasis 'restrictive soil' by encoding dormancy-inducing cues in DTCs. Here we show in a head and neck squamous cell carcinoma (HNSCC) model that strong and specific transforming growth factor-β2 (TGF-β2) signalling in the BM activates the MAPK p38α/β, inducing an (ERK/p38) low signalling ratio. This results in induction of DEC2/SHARP1 and p27, downregulation of cyclin-dependent kinase 4 (CDK4) and dormancy of malignant DTCs. TGF-β2-induced dormancy required TGF-β receptor-I (TGF-β-RI), TGF-β-RIII and SMAD1/5 activation to induce p27. In lungs, a metastasis 'permissive soil' with low TGF-β2 levels, DTC dormancy was short-lived and followed by metastatic growth. Importantly, systemic inhibition of TGF-β-RI or p38α/β activities awakened dormant DTCs, fuelling multi-organ metastasis. Our work reveals a 'seed and soil' mechanism where TGF-β2 and TGF-β-RIII signalling through p38α/β regulates DTC dormancy and defines restrictive (BM) and permissive (lung) microenvironments for HNSCC metastasis.

AB - In patients, non-proliferative disseminated tumour cells (DTCs) can persist in the bone marrow (BM) while other organs (such as lung) present growing metastasis. This suggested that the BM might be a metastasis 'restrictive soil' by encoding dormancy-inducing cues in DTCs. Here we show in a head and neck squamous cell carcinoma (HNSCC) model that strong and specific transforming growth factor-β2 (TGF-β2) signalling in the BM activates the MAPK p38α/β, inducing an (ERK/p38) low signalling ratio. This results in induction of DEC2/SHARP1 and p27, downregulation of cyclin-dependent kinase 4 (CDK4) and dormancy of malignant DTCs. TGF-β2-induced dormancy required TGF-β receptor-I (TGF-β-RI), TGF-β-RIII and SMAD1/5 activation to induce p27. In lungs, a metastasis 'permissive soil' with low TGF-β2 levels, DTC dormancy was short-lived and followed by metastatic growth. Importantly, systemic inhibition of TGF-β-RI or p38α/β activities awakened dormant DTCs, fuelling multi-organ metastasis. Our work reveals a 'seed and soil' mechanism where TGF-β2 and TGF-β-RIII signalling through p38α/β regulates DTC dormancy and defines restrictive (BM) and permissive (lung) microenvironments for HNSCC metastasis.

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U2 - 10.1038/ncb2861

DO - 10.1038/ncb2861

M3 - Article

C2 - 24161934

AN - SCOPUS:84887219089

SN - 1465-7392

VL - 15

SP - 1351

EP - 1361

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 11

ER -

TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling

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