A single-copy Sleeping Beauty transposon mutagenesis screen identifies new PTEN-cooperating tumor suppressor genes.
The overwhelming number of genetic alterations identified through cancer genome sequencing requires complementary approaches to interpret their significance and interactions. Here we developed a novel whole-body insertional mutagenesis screen in mice, which was designed for the discovery of Pten-cooperating tumor suppressors. Toward this aim, we coupled mobilization of a single-copy inactivating Sleeping Beauty transposon to Pten disruption within the same genome. The analysis of 278 transposition-induced prostate, breast and skin tumors detected tissue-specific and shared data sets of known and candidate genes involved in cancer. We validated ZBTB20, CELF2, PARD3, AKAP13 and WAC, which were identified by our screens in multiple cancer types, as new tumor suppressor genes in prostate cancer. We demonstrated their synergy with PTEN in preventing invasion in vitro and confirmed their clinical relevance. Further characterization of Wac in vivo showed obligate haploinsufficiency for this gene (which encodes an autophagy-regulating factor) in a Pten-deficient context. Our study identified complex PTEN-cooperating tumor suppressor networks in different cancer types, with potential clinical implications.
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.|Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA), Oviedo, Spain.|Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
Jorge
J
de la Rosa
Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Julia
J
Weber
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Mathias Josef
MJ
Friedrich
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Yilong
Y
Li
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Lena
L
Rad
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Hannes
http://orcid.org/0000-0001-7573-1703
H
Ponstingl
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Qi
Q
Liang
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Sandra Bernaldo
SB
de Quirós
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Imran
I
Noorani
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Emmanouil
E
Metzakopian
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Alexander
A
Strong
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Meng Amy
MA
Li
Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias, Oviedo, Spain.
Aurora
A
Astudillo
Unidad de Histopatología Molecular, Facultad de Medicina, IUOPA, Universidad de Oviedo, Oviedo, Spain.
María Teresa
MT
Fernández-García
Unidad de Histopatología Molecular, Facultad de Medicina, IUOPA, Universidad de Oviedo, Oviedo, Spain.
María Soledad
MS
Fernández-García
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.|School of Medicine, University of Western Australia, Crawley, Western Australia, Australia.
Gary J
GJ
Hoffman
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Rocío
R
Fuente
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
George S
http://orcid.org/0000-0003-4337-8022
GS
Vassiliou
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.|Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Roland
R
Rad
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.|Centro de Investigación Biomédica en Red de Cáncer, Spain.
Carlos
C
López-Otín
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Allan
A
Bradley
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.|Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA), Oviedo, Spain.
Juan
http://orcid.org/0000-0001-7561-7759
J
Cadiñanos
D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D004251:DNA Transposable Elements / Q000235:genetics*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D018628:Gene Dosage; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011467:Prostate / Q000166:cytology / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics*; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics
D004251:DNA Transposable Elements; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse