TY - JOUR
T1 - A single-copy Sleeping Beauty transposon mutagenesis screen identifies new PTEN-cooperating tumor suppressor genes
AU - De La Rosa, Jorge
AU - Weber, Julia
AU - Friedrich, Mathias Josef
AU - Li, Yilong
AU - Rad, Lena
AU - Ponstingl, Hannes
AU - Liang, Qi
AU - De Quirós, Sandra Bernaldo
AU - Noorani, Imran
AU - Metzakopian, Emmanouil
AU - Strong, Alexander
AU - Li, Meng Amy
AU - Astudillo, Aurora
AU - Fernández-García, María Teresa
AU - Fernández-García, María Soledad
AU - Hoffman, Gary J.
AU - Fuente, Rocío
AU - Vassiliou, George S.
AU - Rad, Roland
AU - López-Otín, Carlos
AU - Bradley, Allan
AU - Cadiñanos, Juan
PY - 2017/5/1
Y1 - 2017/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85015656499&partnerID=8YFLogxK
U2 - 10.1038/ng.3817
DO - 10.1038/ng.3817
M3 - Article
C2 - 28319090
AN - SCOPUS:85015656499
SN - 1061-4036
VL - 49
SP - 730
EP - 741
JO - Nature Genetics
JF - Nature Genetics
IS - 5
ER -
