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

Ragusa, S. et al. (2014) PROX1 promotes metabolic adaptation and fuels outgrowth of Wnt high metastatic colon cancer cells. Cell Reports, 8(6), pp. 1957-1973. (doi: 10.1016/j.celrep.2014.08.041) (PMID:25242332)

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.

• Item Type: Articles
• Additional Information: The work was supported by Swiss National Science Foundation (PPP0033-114898 to T.V.P. and 31003A-141225 to G.M.), Swiss Bridge Foundation, NCCR Molecular Oncology, Association for the International Cancer Research UK, Oncosuisse (KLS-02570-02-2010), CRUK, ERC investigator award ‘‘COLONCAN’’ (to O.J.S.), EU FP7 grant no. 278568 ‘‘PRIMES,’’ and Medic Foundation.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cammareri, Dr Patrizia and Ceteci, Dr Fatih and Sansom, Professor Owen
• Authors: Ragusa, S., Cheng, J., Ivanov, K. I., Zangger, N., Ceteci, F., Bernier-Latmani, J., Milatos, S., Joseph, J.-M., Tercier, S., Bouzourene, H., Bosman, F. T., Letovanec, I., Marra, G., Gonzalez, M., Cammareri, P., Sansom, O. J., Delorenzi, M., and Petrova, T. V.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cell Reports
• Publisher: Elsevier
• ISSN: 2211-1247
• ISSN (Online): 2211-1247
• Published Online: 18 September 2014
• Copyright Holders: Copyright © 2014 The Authors
• First Published: First published in Cell Reports 8(6):1957-1973
• Publisher Policy: Reproduced under a Creative Commons license