Abstract
As we enter the era of precision medicine, characterization of cancer genomes will directly influence therapeutic decisions in the clinic. Here we describe a platform enabling functionalization of rare gene mutations through their high-throughput construction, molecular barcoding and delivery to cancer models for in vivo tumour driver screens. We apply these technologies to identify oncogenic drivers of pancreatic ductal adenocarcinoma (PDAC). This approach reveals oncogenic activity for rare gene aberrations in genes including NAD Kinase (NADK), which regulates NADP(H) homeostasis and cellular redox state. We further validate mutant NADK, whose expression provides gain-of-function enzymatic activity leading to a reduction in cellular reactive oxygen species and tumorigenesis, and show that depletion of wild-type NADK in PDAC cell lines attenuates cancer cell growth in vitro and in vivo. These data indicate that annotating rare aberrations can reveal important cancer signalling pathways representing additional therapeutic targets.
| Original language | English (US) |
|---|---|
| Article number | 10500 |
| Journal | Nature Communications |
| Volume | 7 |
| DOIs | |
| State | Published - Jan 25 2016 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
Cite this
Functional annotation of rare gene aberration drivers of pancreatic cancer. / Tsang, Yiu Huen; Dogruluk, Turgut; Tedeschi, Philip M.; Wardwell-Ozgo, Joanna; Lu, Hengyu; Espitia, Maribel; Nair, Nikitha; Minelli, Rosalba; Chong, Zechen; Chen, Fengju; Chang, Qing Edward; Dennison, Jennifer B.; Dogruluk, Armel; Li, Min; Ying, Haoqiang; Bertino, Joseph R.; Gingras, Marie Claude; Ittmann, Michael; Kerrigan, John; Chen, Ken; Creighton, Chad J.; Eterovic, Karina; Mills, Gordon; Scott, Kenneth L.
In: Nature Communications, Vol. 7, 10500, 25.01.2016.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Functional annotation of rare gene aberration drivers of pancreatic cancer
AU - Tsang, Yiu Huen
AU - Dogruluk, Turgut
AU - Tedeschi, Philip M.
AU - Wardwell-Ozgo, Joanna
AU - Lu, Hengyu
AU - Espitia, Maribel
AU - Nair, Nikitha
AU - Minelli, Rosalba
AU - Chong, Zechen
AU - Chen, Fengju
AU - Chang, Qing Edward
AU - Dennison, Jennifer B.
AU - Dogruluk, Armel
AU - Li, Min
AU - Ying, Haoqiang
AU - Bertino, Joseph R.
AU - Gingras, Marie Claude
AU - Ittmann, Michael
AU - Kerrigan, John
AU - Chen, Ken
AU - Creighton, Chad J.
AU - Eterovic, Karina
AU - Mills, Gordon
AU - Scott, Kenneth L.
PY - 2016/1/25
Y1 - 2016/1/25
N2 - As we enter the era of precision medicine, characterization of cancer genomes will directly influence therapeutic decisions in the clinic. Here we describe a platform enabling functionalization of rare gene mutations through their high-throughput construction, molecular barcoding and delivery to cancer models for in vivo tumour driver screens. We apply these technologies to identify oncogenic drivers of pancreatic ductal adenocarcinoma (PDAC). This approach reveals oncogenic activity for rare gene aberrations in genes including NAD Kinase (NADK), which regulates NADP(H) homeostasis and cellular redox state. We further validate mutant NADK, whose expression provides gain-of-function enzymatic activity leading to a reduction in cellular reactive oxygen species and tumorigenesis, and show that depletion of wild-type NADK in PDAC cell lines attenuates cancer cell growth in vitro and in vivo. These data indicate that annotating rare aberrations can reveal important cancer signalling pathways representing additional therapeutic targets.
AB - As we enter the era of precision medicine, characterization of cancer genomes will directly influence therapeutic decisions in the clinic. Here we describe a platform enabling functionalization of rare gene mutations through their high-throughput construction, molecular barcoding and delivery to cancer models for in vivo tumour driver screens. We apply these technologies to identify oncogenic drivers of pancreatic ductal adenocarcinoma (PDAC). This approach reveals oncogenic activity for rare gene aberrations in genes including NAD Kinase (NADK), which regulates NADP(H) homeostasis and cellular redox state. We further validate mutant NADK, whose expression provides gain-of-function enzymatic activity leading to a reduction in cellular reactive oxygen species and tumorigenesis, and show that depletion of wild-type NADK in PDAC cell lines attenuates cancer cell growth in vitro and in vivo. These data indicate that annotating rare aberrations can reveal important cancer signalling pathways representing additional therapeutic targets.
UR - http://www.scopus.com/inward/record.url?scp=84955444058&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84955444058&partnerID=8YFLogxK
U2 - 10.1038/ncomms10500
DO - 10.1038/ncomms10500
M3 - Article
C2 - 26806015
AN - SCOPUS:84955444058
VL - 7
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 10500
ER -