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.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Department of Otolaryngology, Tisch Cancer Institute, Mount Sinai School of Medicine, New York 10029, USA.
authors.forename: Paloma
authors.initials: P
authors.lastname: Bragado
authors.forename: Yeriel
authors.initials: Y
authors.lastname: Estrada
authors.forename: Falguni
authors.initials: F
authors.lastname: Parikh
authors.forename: Sarah
authors.initials: S
authors.lastname: Krause
authors.forename: Carla
authors.initials: C
authors.lastname: Capobianco
authors.forename: Hernan G
authors.initials: HG
authors.lastname: Farina
authors.forename: Denis M
authors.initials: DM
authors.lastname: Schewe
authors.forename: Julio A
authors.initials: JA
authors.lastname: Aguirre-Ghiso
mesh_terms: D000818:Animals; D019070:Cell Lineage; D004789:Enzyme Activation; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D011509:Proteoglycans / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D053781:Transforming Growth Factor beta2 / Q000502:physiology*; D059016:Tumor Microenvironment; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; C509042:Tgfb2 protein, mouse; D053781:Transforming Growth Factor beta2; C071736:betaglycan; D048051:p38 Mitogen-Activated Protein Kinases