title: Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation.
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.
authors.affiliation: Oncology Programme, Institute for Research in Biomedicine, 08028 Barcelona, Spain.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Calon
authors.forename: Elisa
authors.initials: E
authors.lastname: Espinet
authors.forename: Sergio
authors.initials: S
authors.lastname: Palomo-Ponce
authors.forename: Daniele V F
authors.initials: DV
authors.lastname: Tauriello
authors.forename: Mar
authors.initials: M
authors.lastname: Iglesias
authors.forename: María Virtudes
authors.initials: MV
authors.lastname: Céspedes
authors.forename: Marta
authors.initials: M
authors.lastname: Sevillano
authors.forename: Cristina
authors.initials: C
authors.lastname: Nadal
authors.forename: Peter
authors.initials: P
authors.lastname: Jung
authors.forename: Xiang H-F
authors.initials: XH
authors.lastname: Zhang
authors.forename: Daniel
authors.initials: D
authors.lastname: Byrom
authors.forename: Antoni
authors.initials: A
authors.lastname: Riera
authors.forename: David
authors.initials: D
authors.lastname: Rossell
authors.forename: Ramón
authors.initials: R
authors.lastname: Mangues
authors.forename: Joan
authors.initials: J
authors.lastname: Massagué
authors.forename: Elena
authors.initials: E
authors.lastname: Sancho
authors.forename: Eduard
authors.initials: E
authors.lastname: Batlle
mesh_terms: D000818:Animals; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology*; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D019073:HT29 Cells; D006801:Humans; D017370:Interleukin-11 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051379:Mice; D009362:Neoplasm Metastasis / Q000188:drug therapy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D012008:Recurrence; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: C494200:Il6st protein, mouse; D017370:Interleukin-11; D018125:Receptors, Transforming Growth Factor beta; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016212:Transforming Growth Factor beta; D050822:Cytokine Receptor gp130; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse