title: PROX1 promotes metabolic adaptation and fuels outgrowth of Wnt(high) metastatic colon cancer cells.
abstract: The Wnt pathway is abnormally activated in the majority of colorectal cancers, and significant knowledge has been gained in understanding its role in tumor initiation. However, the mechanisms of metastatic outgrowth in colorectal cancer remain a major challenge. We report that autophagy-dependent metabolic adaptation and survival of metastatic colorectal cancer cells is regulated by the target of oncogenic Wnt signaling, homeobox transcription factor PROX1, expressed by a subpopulation of colon cancer progenitor/stem cells. We identify direct PROX1 target genes and show that repression of a pro-apoptotic member of the BCL2 family, BCL2L15, is important for survival of PROX1(+) cells under metabolic stress. PROX1 inactivation after the establishment of metastases prevented further growth of lesions. Furthermore, autophagy inhibition efficiently targeted metastatic PROX1(+) cells, suggesting a potential therapeutic approach. These data identify PROX1 as a key regulator of the transcriptional network contributing to metastases outgrowth in colorectal cancer.
authors.affiliation: Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne 1066, Switzerland.
authors.forename: Simone
authors.initials: S
authors.lastname: Ragusa
authors.affiliation: Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne 1066, Switzerland.
authors.forename: Jianpin
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne 1066, Switzerland.
authors.forename: Konstantin I
authors.initials: KI
authors.lastname: Ivanov
authors.affiliation: SIB Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland.
authors.forename: Nadine
authors.initials: N
authors.lastname: Zangger
authors.affiliation: Cancer Research UK Beatson Institute, G61 1BD Glasgow, UK.
authors.forename: Fatih
authors.initials: F
authors.lastname: Ceteci
authors.affiliation: Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne 1066, Switzerland.
authors.forename: Jeremiah
authors.initials: J
authors.lastname: Bernier-Latmani
authors.affiliation: Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne 1066, Switzerland.
authors.forename: Stavros
authors.initials: S
authors.lastname: Milatos
authors.affiliation: Service de Chirurgie Pédiatrique, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne 1011, Switzerland.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Joseph
authors.affiliation: Service de Chirurgie Pédiatrique, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne 1011, Switzerland.
authors.forename: Stephane
authors.initials: S
authors.lastname: Tercier
authors.affiliation: UNISciences, University of Lausanne, UniLabs, Lausanne 1066, Switzerland.
authors.forename: Hanifa
authors.initials: H
authors.lastname: Bouzourene
authors.affiliation: Institut Universitaire de Pathologie, CHUV, Lausanne 1011, Switzerland.
authors.forename: Fredrik T
authors.initials: FT
authors.lastname: Bosman
authors.affiliation: Institut Universitaire de Pathologie, CHUV, Lausanne 1011, Switzerland.
authors.forename: Igor
authors.initials: I
authors.lastname: Letovanec
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, Zurich 8057, Switzerland.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Marra
authors.affiliation: Division of Thoracic Surgery, CHUV, Lausanne 1011, Switzerland.
authors.forename: Michel
authors.initials: M
authors.lastname: Gonzalez
authors.affiliation: Cancer Research UK Beatson Institute, G61 1BD Glasgow, UK.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Cammareri
authors.affiliation: Cancer Research UK Beatson Institute, G61 1BD Glasgow, UK.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne 1066, Switzerland; SIB Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland; Ludwig Center for Cancer Research, University of Lausanne, Lausanne 1066, Switzerland.
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.affiliation: Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne 1066, Switzerland; Department of Biochemistry, University of Lausanne, Lausanne 1066, Switzerland; Swiss Institute for Cancer Research, EPFL, Lausanne 1015, Switzerland. Electronic address: tatiana.petrova@unil.ch.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Petrova
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000633:toxicity; D003110:Colonic Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D051379:Mice; D016688:Mice, Inbred NOD; D014411:Neoplastic Stem Cells / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D013312:Stress, Physiological; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: C481505:BCL2L15 protein, human; D018398:Homeodomain Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D002738:Chloroquine