title: Stromal gene expression defines poor-prognosis subtypes in colorectal cancer.
abstract: Recent molecular classifications of colorectal cancer (CRC) based on global gene expression profiles have defined subtypes displaying resistance to therapy and poor prognosis. Upon evaluation of these classification systems, we discovered that their predictive power arises from genes expressed by stromal cells rather than epithelial tumor cells. Bioinformatic and immunohistochemical analyses identify stromal markers that associate robustly with disease relapse across the various classifications. Functional studies indicate that cancer-associated fibroblasts (CAFs) increase the frequency of tumor-initiating cells, an effect that is dramatically enhanced by transforming growth factor (TGF)-β signaling. Likewise, we find that all poor-prognosis CRC subtypes share a gene program induced by TGF-β in tumor stromal cells. Using patient-derived tumor organoids and xenografts, we show that the use of TGF-β signaling inhibitors to block the cross-talk between cancer cells and the microenvironment halts disease progression.
authors.affiliation: Institute for Research in Biomedicine (IRB) Barcelona, Barcelona, Spain.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Calon
authors.affiliation: Institute for Research in Biomedicine (IRB) Barcelona, Barcelona, Spain.
authors.forename: Enza
authors.initials: E
authors.lastname: Lonardo
authors.affiliation: Institute for Research in Biomedicine (IRB) Barcelona, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Berenguer-Llergo
authors.affiliation: Institute for Research in Biomedicine (IRB) Barcelona, Barcelona, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Espinet
authors.affiliation: Institute for Research in Biomedicine (IRB) Barcelona, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Hernando-Momblona
authors.affiliation: 1] Department of Pathology, Hospital del Mar, Barcelona, Spain. [2] Cancer Research Program, Hospital del Mar Research Institute (IMIM), Barcelona, Spain. [3] Universitat Autónoma de Barcelona, Barcelona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Iglesias
authors.affiliation: Institute for Research in Biomedicine (IRB) Barcelona, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Sevillano
authors.affiliation: Institute for Research in Biomedicine (IRB) Barcelona, Barcelona, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Palomo-Ponce
authors.affiliation: Institute for Research in Biomedicine (IRB) Barcelona, Barcelona, Spain.
authors.forename: Daniele V F
authors.identifier: 0000000315223496
authors.initials: DV
authors.lastname: Tauriello
authors.affiliation: Institute for Research in Biomedicine (IRB) Barcelona, Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Byrom
authors.affiliation: Institute for Research in Biomedicine (IRB) Barcelona, Barcelona, Spain.
authors.forename: Carme
authors.initials: C
authors.lastname: Cortina
authors.affiliation: Institute for Research in Biomedicine (IRB) Barcelona, Barcelona, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Morral
authors.affiliation: Institute for Research in Biomedicine (IRB) Barcelona, Barcelona, Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Barceló
authors.affiliation: Institute for Research in Biomedicine (IRB) Barcelona, Barcelona, Spain.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Tosi
authors.affiliation: Institute for Research in Biomedicine (IRB) Barcelona, Barcelona, Spain.
authors.forename: Antoni
authors.identifier: 0000000171427675
authors.initials: A
authors.lastname: Riera
authors.affiliation: Institute for Research in Biomedicine (IRB) Barcelona, Barcelona, Spain.
authors.forename: Camille Stephan-Otto
authors.identifier: 000000018045320X
authors.initials: CS
authors.lastname: Attolini
authors.affiliation: Institute for Research in Biomedicine (IRB) Barcelona, Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Rossell
authors.affiliation: Institute for Research in Biomedicine (IRB) Barcelona, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Sancho
authors.affiliation: 1] Institute for Research in Biomedicine (IRB) Barcelona, Barcelona, Spain. [2] Institució Catalana de Recerca i Estudis Avançats (iCREA), Barcelona, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Batlle
mesh_terms: D000818:Animals; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000145:classification / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D046228:Microarray Analysis; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D059467:Transcriptome