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

Alexandre Calon, Elisa Espinet, Sergio Palomo-Ponce, Daniele V.F. Tauriello, Mar Iglesias, María Virtudes Céspedes, Marta Sevillano, Cristina Nadal, Peter Jung, Xiang H.F. Zhang, Daniel Byrom, Antoni Riera, David Rossell, Ramón Mangues, Joan Massagué, Elena Sancho*, Eduard Batlle

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

849 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)571-584
Number of pages14
JournalCancer Cell
Volume22
Issue number5
DOIs
Publication statusPublished - 13 Nov 2012
Externally publishedYes

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