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Cell Rep. 2014 Sep 25;8(6):1957-1973. doi: 10.1016/j.celrep.2014.08.041. Epub 2014 Sep 18.

PROX1 promotes metabolic adaptation and fuels outgrowth of Wnt(high) metastatic colon cancer cells.

Author information

1
Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne 1066, Switzerland.
2
SIB Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland.
3
Cancer Research UK Beatson Institute, G61 1BD Glasgow, UK.
4
Service de Chirurgie PĂ©diatrique, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne 1011, Switzerland.
5
UNISciences, University of Lausanne, UniLabs, Lausanne 1066, Switzerland.
6
Institut Universitaire de Pathologie, CHUV, Lausanne 1011, Switzerland.
7
Institute of Molecular Cancer Research, University of Zurich, Zurich 8057, Switzerland.
8
Division of Thoracic Surgery, CHUV, Lausanne 1011, Switzerland.
9
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.
10
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.

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.

PMID:
25242332
DOI:
10.1016/j.celrep.2014.08.041
[Indexed for MEDLINE]
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