Dependency of Colorectal Cancer on a TGF-β-Driven Program in Stromal Cells for Metastasis Initiation

SummaryA 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (222 K)Download as PowerPoint slideHighlights► TGF-β pathway mutant cells require a stromal TGF-β program for metastasis ► CRC patients with low levels of stromal TGF-β program do not relapse ► Pharmacological blockade of TGF-β stromal signaling prevents metastasis initiation ► A TGF-β/IL-11/GP130 signaling cycle confers metastatic organ colonization capacity