Upregulated WEE1 protects endothelial cells of colorectal cancer liver metastases.
Surgical resection of colorectal cancer liver metastases (CLM) can be curative, yet 80% of patients are unsuitable for this treatment. As angiogenesis is a determinant of CLM progression we isolated endothelial cells from CLM and sought a mechanism which is upregulated, essential for angiogenic properties of these cells and relevant to emerging therapeutic options. Matched CLM endothelial cells (CLMECs) and endothelial cells of normal adjacent liver (LiECs) were superficially similar but transcriptome sequencing revealed molecular differences, one of which was unexpected upregulation and functional significance of the checkpoint kinase WEE1. Western blotting confirmed that WEE1 protein was upregulated in CLMECs. Knockdown of WEE1 by targeted short interfering RNA or the WEE1 inhibitor AZD1775 suppressed proliferation and migration of CLMECs. Investigation of the underlying mechanism suggested induction of double-stranded DNA breaks due to nucleotide shortage which then led to caspase 3-dependent apoptosis. The implication for CLMEC tube formation was striking with AZD1775 inhibiting tube branch points by 83%. WEE1 inhibitors might therefore be a therapeutic option for CLM and could be considered more broadly as anti-angiogenic agents in cancer treatment.
School of Medicine, University of Leeds, Leeds LS2 9JT, UK.
Peter J
PJ
Webster
School of Medicine, University of Leeds, Leeds LS2 9JT, UK.
Anna T
AT
Littlejohns
School of Medicine, University of Leeds, Leeds LS2 9JT, UK.
Hannah J
HJ
Gaunt
School of Medicine, University of Leeds, Leeds LS2 9JT, UK.
Richard S
RS
Young
School of Medicine, University of Leeds, Leeds LS2 9JT, UK.
Baptiste
B
Rode
School of Medicine, University of Leeds, Leeds LS2 9JT, UK.
Judith E
JE
Ritchie
School of Medicine, University of Leeds, Leeds LS2 9JT, UK.
Lucy F
LF
Stead
School of Medicine, University of Leeds, Leeds LS2 9JT, UK.
Sally
S
Harrison
School of Medicine, University of Leeds, Leeds LS2 9JT, UK.|MRC Medical Bioinformatics Centre, University of Leeds, Leeds LS2 9NL, UK.
Alastair
A
Droop
School of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
Heather L
HL
Martin
School of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
Darren C
DC
Tomlinson
School of Medicine, University of Leeds, Leeds LS2 9JT, UK.
Adam J
AJ
Hyman
School of Medicine, University of Leeds, Leeds LS2 9JT, UK.
Hollie L
HL
Appleby
School of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
Sally
S
Boxall
School of Medicine, University of Leeds, Leeds LS2 9JT, UK.
Alexander F
AF
Bruns
School of Medicine, University of Leeds, Leeds LS2 9JT, UK.
Jing
J
Li
Department of Hepatobiliary and Transplant Surgery, St. James's University Hospital, Leeds LS9 7TF, UK.
Raj K
RK
Prasad
Department of Hepatobiliary and Transplant Surgery, St. James's University Hospital, Leeds LS9 7TF, UK.
J Peter A
JPA
Lodge
School of Medicine, University of Leeds, Leeds LS2 9JT, UK.|Department of Colorectal Surgery, St. James's University Hospital, Leeds LS9 7TF, UK.
Dermot A
DA
Burke
School of Medicine, University of Leeds, Leeds LS2 9JT, UK.
David J
DJ
Beech
D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D053903:DNA Breaks, Double-Stranded; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D053148:Caspase 3
DNA damage; angiogenesis; checkpoint kinase; colorectal cancer; endothelial cell