Journal article

Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice.

  • Ragusa S Department of Oncology, University of Lausanne and CHUV, Epalinges, Switzerland.
  • Prat-Luri B Department of Oncology, University of Lausanne and CHUV, Epalinges, Switzerland.
  • González-Loyola A Department of Oncology, University of Lausanne and CHUV, Epalinges, Switzerland.
  • Nassiri S Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne, Switzerland.
  • Squadrito ML Swiss Institute for Experimental Cancer Research, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland.
  • Guichard A Swiss Institute for Experimental Cancer Research, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland.
  • Cavin S Division of Thoracic Surgery, CHUV, Lausanne, Switzerland.
  • Gjorevski N Institute of Bioengineering, School of Life Sciences, EPFL, Lausanne, Switzerland.
  • Barras D Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne, Switzerland.
  • Marra G Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
  • Lutolf MP Institute of Bioengineering, School of Life Sciences, EPFL, Lausanne, Switzerland.
  • Perentes J Division of Thoracic Surgery, CHUV, Lausanne, Switzerland.
  • Corse E Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, (pRED), Schlieren, Switzerland.
  • Bianchi R Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, (pRED), Schlieren, Switzerland.
  • Wetterwald L Department of Oncology, University of Lausanne and CHUV, Epalinges, Switzerland.
  • Kim J Department of Oncology, University of Lausanne and CHUV, Epalinges, Switzerland.
  • Oliver G Center for Vascular and Developmental Biology, Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
  • Delorenzi M Department of Oncology, University of Lausanne and CHUV, Epalinges, Switzerland.
  • De Palma M Swiss Institute for Experimental Cancer Research, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland.
  • Petrova TV Department of Oncology, University of Lausanne and CHUV, Epalinges, Switzerland.
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  • 2020-02-05
Published in:
  • The Journal of clinical investigation. - 2020
English Mutations 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.
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  • English
Open access status
green
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https://sonar.ch/global/documents/95249
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