TGF-?2 dictates disseminated tumour cell fate in target organs through TGF-?-RIII and p38?/? 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-?2 (TGF-?2) signalling in the BM activates the MAPK p38?/?, 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-?2-induced dormancy required TGF-? receptor-I (TGF-?-RI), TGF-?-RIII and SMAD1/5 activation to induce p27. In lungs, a metastasis 'permissive soil' with low TGF-?2 levels, DTC dormancy was short-lived and followed by metastatic growth. Importantly, systemic inhibition of TGF-?-RI or p38?/? activities awakened dormant DTCs, fuelling multi-organ metastasis. Our work reveals a 'seed and soil' mechanism where TGF-?2 and TGF-?-RIII signalling through p38?/? regulates DTC dormancy and defines restrictive (BM) and permissive (lung) microenvironments for HNSCC metastasis.

SUBMITTER: Bragado P 

PROVIDER: S-EPMC4006312 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature