Functional annotation of rare gene aberration drivers of pancreatic cancer

Cartoon of different color cells in a petri dish

Investigators use a screening platform to create barcoded clones carrying selected mutations. The clones are used to create xenografts to analyze the function of the mutations. Image courtesy of Open Clipart.

Tsang YH, Dogruluk T, Tedeschi PM, Wardwell-Ozgo J, Lu H, Espitia M, Nair N, Minelli R, Chong Z, Chen F, Chang QE, Dennison JB, Dogruluk A, Li M, Ying H, Bertino JR, Gingras MC, Ittmann M, Kerrigan J, Chen K, Creighton CJ, Eterovic K, Mills GB, Scott KL

Nature Communications

January 25, 2016

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. (Publication Abstract)

Program:
CTD²
Last updated: October 31, 2017