Alexandre Calon 1 , Enza Lonardo 1 , Antonio Berenguer-Llergo 1 , Elisa Espinet 1 , Xavier Hernando-Momblona 1 , Mar Iglesias 2 , Marta Sevillano 1 , Sergio Palomo-Ponce 1 , Daniele V F Tauriello 1 , Daniel Byrom 1 , Carme Cortina 1 , Clara Morral 1 , Carles Barceló 1 , Sebastien Tosi 1 , Antoni Riera 1 , Camille Stephan-Otto Attolini 1 , David Rossell 1 , Elena Sancho 1 , Eduard Batlle 3
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.