FOXC2 promotes vasculogenic mimicry and resistance to anti-angiogenic therapy
Ian G. Cannell,
Kirsty Sawicka,
Isabella Pearsall,
Sophia A. Wild,
Lauren Deighton,
Sarah M. Pearsall,
Giulia Lerda,
Fadwa Joud,
Showkhin Khan,
Alejandra Bruna,
Kathryn L. Simpson,
Claire M. Mulvey,
Fiona Nugent,
Fatime Qosaj,
Dario Bressan,
Caroline Dive,
Carlos Caldas,
Gregory J. Hannon
Affiliations
Ian G. Cannell
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; New York Genome Center, 101 Avenue of the Americas, New York, NY 10013, USA; Corresponding author
Kirsty Sawicka
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; New York Genome Center, 101 Avenue of the Americas, New York, NY 10013, USA
Isabella Pearsall
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; New York Genome Center, 101 Avenue of the Americas, New York, NY 10013, USA
Sophia A. Wild
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
Lauren Deighton
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
Sarah M. Pearsall
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; Cancer Research UK Cancer Biomarker Centre, Manchester M20 4BX, UK; CRUK Manchester Institute, Manchester M20 4BX, UK
Giulia Lerda
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
Fadwa Joud
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
Showkhin Khan
New York Genome Center, 101 Avenue of the Americas, New York, NY 10013, USA
Alejandra Bruna
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; Preclinical Modelling of Paediatric Cancer Evolution Team, The Institute of Cancer Research, Cotswold Road, Sutton, Surrey SM2 5N, UK
Kathryn L. Simpson
Cancer Research UK Cancer Biomarker Centre, Manchester M20 4BX, UK; CRUK Manchester Institute, Manchester M20 4BX, UK
Claire M. Mulvey
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
Fiona Nugent
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
Fatime Qosaj
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
Dario Bressan
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
Caroline Dive
Cancer Research UK Cancer Biomarker Centre, Manchester M20 4BX, UK; CRUK Manchester Institute, Manchester M20 4BX, UK
Carlos Caldas
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; Department of Oncology and Breast Cancer Programme, CRUK Cambridge Centre, Cambridge University Hospitals NHS and University of Cambridge, Cambridge CB2 2QQ, UK
Gregory J. Hannon
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; New York Genome Center, 101 Avenue of the Americas, New York, NY 10013, USA; Corresponding author
Summary: Vasculogenic mimicry (VM) describes the formation of pseudo blood vessels constructed of tumor cells that have acquired endothelial-like properties. VM channels endow the tumor with a tumor-derived vascular system that directly connects to host blood vessels, and their presence is generally associated with poor patient prognosis. Here we show that the transcription factor, Foxc2, promotes VM in diverse solid tumor types by driving ectopic expression of endothelial genes in tumor cells, a process that is stimulated by hypoxia. VM-proficient tumors are resistant to anti-angiogenic therapy, and suppression of Foxc2 augments response. This work establishes co-option of an embryonic endothelial transcription factor by tumor cells as a key mechanism driving VM proclivity and motivates the search for VM-inhibitory agents that could form the basis of combination therapies with anti-angiogenics.
