Dependency of Colorectal Cancer on a TGF-
Menée in vitro, in vivo et à partir de données portant sur 345 patients atteints d'un cancer colorectal métastatique, cette étude met en évidence des mécanismes par lesquels l'activité du facteur de croissance transformant bêta dans les cellules du stroma favorise le processus métastatique
A large proportion of colorectal cancers (CRCs) display mutational inactivation of the TGF-
β
pathway, yet, paradoxically, they are characterized by elevated TGF-
β
production. Here, we unveil a prometastatic program induced by TGF-
β
in the microenvironment that associates with a high risk of CRC relapse upon treatment. The activity of TGF-
β
on stromal cells increases the efficiency of organ colonization by CRC cells, whereas mice treated with a pharmacological inhibitor of TGFBR1 are resilient to metastasis formation. Secretion of IL11 by TGF-
β
-stimulated cancer-associated fibroblasts (CAFs) triggers GP130/STAT3 signaling in tumor cells. This crosstalk confers a survival advantage to metastatic cells. The dependency on the TGF-
β
stromal program for metastasis initiation could be exploited to improve the diagnosis and treatment of CRC.
º TGF-
β
pathway mutant cells require a stromal TGF-
β
program for metastasis
º CRC patients with low levels of stromal TGF-
β
program do not relapse
º Pharmacological blockade of TGF-
β
stromal signaling prevents metastasis initiation
º A TGF-
β
/IL-11/GP130 signaling cycle confers metastatic organ colonization capacity
Cancer cell , résumé, 2011