Ragusa, SimonePrat-Luri, BorjaGonzález-Loyola, AlejandraNassiri, SinaSquadrito, Mario LeonardoGuichard, AlanCavin, SabrinaGjorevski, NikolceBarras, DavidMarra, GiancarloLutolf, Matthias P.Perentes, JeanCorse, EmilyBianchi, RobertaWetterwald, LaurelineKim, JaeryungOliver, GuillermoDelorenzi, MauroDe Palma, MichelePetrova, Tatiana V.2020-02-142020-02-142020-02-142020-02-0410.1172/JCI129558https://infoscience.epfl.ch/handle/20.500.14299/165558Mutations in APC promote colorectal cancer (CRC) progression through uncontrolled WNT signaling. Patients with desmoplastic CRC have a significantly worse prognosis and do not benefit from chemotherapy, but the mechanisms underlying the differential responses of APC-mutant CRCs to chemotherapy are not well understood. We report that expression of the transcription factor prospero homeobox 1 (PROX1) was reduced in desmoplastic APC-mutant human CRCs. In genetic Apc-mutant mouse models, loss of Prox1 promoted the growth of desmoplastic, angiogenic, and immunologically silent tumors through derepression of Mmp14. Although chemotherapy inhibited Prox1-proficient tumors, it promoted further stromal activation, angiogenesis, and invasion in Prox1-deficient tumors. Blockade of vascular endothelial growth factor A (VEGFA) and angiopoietin-2 (ANGPT2) combined with CD40 agonistic antibodies promoted antiangiogenic and immunostimulatory reprogramming of Prox1-deficient tumors, destroyed tumor fibrosis, and unleashed T cell–mediated killing of cancer cells. These results pinpoint the mechanistic basis of chemotherapy-induced hyperprogression and illustrate a therapeutic strategy for chemoresistant and desmoplastic CRCs.Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in micetext::journal::journal article::research article