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.
Show more…
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.
-
Language
-
-
Open access status
-
green
-
Identifiers
-
-
Persistent URL
-
https://sonar.ch/global/documents/95249
Statistics
Document views: 19
File downloads: