Ku, A. A. | bioRxiv Science

bioRxiv2020

UDP-glucose pyrophosphorylase 2, a regulator of glycosylation and glycogen, is essential for pancreatic cancer growth

Pancreatic ductal adenocarcinomas (PDACs) have enhanced nutrient uptake requirements and rapid metabolic processing. The enzyme UDP-glucose pyrophosphorylase 2 (UGP2) rests at the convergence of multiple metabolic pathways, however the role of UGP2 in tumor maintenance and cancer metabolism remains unclear. Here, we identify an essential role for UGP2 in the maintenance of PDAC growth in both in vitro and in vivo tumor models. Transcription of UGP2 is directly regulated by the YAP/TEAD complex. Loss of UGP2 leads to decreased intracellular glycogen and defects in N-glycosylation targets important for cell growth including epidermal growth factor receptor (EGFR). In murine xenograft models, knockdown of UGP2 halted tumor growth and repressed expression of EGFR. The critical roles of UGP2 in cancer maintenance, metabolism, and protein glycosylation may offer new avenues of therapy for otherwise intractable PDACs. Impact StatementConvergent findings reveal that UDP-glucose pyrophosphorylase 2 has a central role in growth and metabolism of pancreatic ductal adenocarcinomas, highlighting novel therapeutic possibilities for this deadly cancer.

cancer biology↗

bioRxiv2019

Integration of pathway, cellular and genetic context reveals principles of synthetic lethality that affect reproducibility

Synthetic lethal screens have the potential to identify new vulnerabilities incurred by specific cancer mutations but have been hindered by lack of agreement between studies. Using KRAS as a model, we identified that published synthetic lethal screens significantly overlap at the pathway rather than gene level. Analysis of pathways encoded as protein networks identified synthetic lethal candidates that were more reproducible than those previously reported. Lack of overlap likely stems from biological rather than technical limitations as most synthetic lethal phenotypes were strongly modulated by changes in cellular conditions or genetic context, the latter determined using a pairwise genetic interaction map that identified numerous interactions that suppress synthetic lethal effects. Accounting for pathway, cellular and genetic context nominates a DNA repair dependency in KRAS-mutant cells, mediated by a network containing BRCA1. We provide evidence for why most reported synthetic lethals are not reproducible which is addressable using a multi-faceted testing framework.\n\nSTATEMENT OF SIGNIFICANCESynthetic lethal screens have the power to identify new targets in cancer, although have thus far come up short of expectation. We use computational and experimental approaches to delineate principles for identifying robust synthetic lethal targets that could aid in the development of effective new therapeutic strategies for genetically defined cancers.

cancer biology↗