Shane Kelly

No-take' marine reserves provide a valuable tool for managing marine resources as well as for providing relatively undisturbed habitat with which to assess modifications to ecosystems. We studied 2 marine reserves in northeastern New Zealand, the Leigh Marine Reserve (established 1975) and Tawharanui Marine Park (established 1982) in order to assess whether changes in protected predator populations had resulted in other indirect changes to grazers and consequently to algal abundance. Estimates of abundance of the most common demersal predatory fish Pagrus auratus indicated that adults of this species (i.e. large enough to prey upon urchins) were at least 5.75 and 8.70 times more abundant inside reserves than in adjacent unprotected areas. Overall, P auratus were also much larger inside reserves with mean total lengths of 316 mm compared with 186 mm in fished areas. The spiny lobster Jasus edwardsii displayed similar trends, and was approximately 1.6 to 3.7 times more abundant inside the reserves than outside. Lobsters within the reserves had a mean carapace length of 109.9 mm, compared with 93.5 mm outside the reserves. In one of the reserves, densities of the sea urchin Evechinus chloroticus had declined from 4.9 to 1.4 m-2 since 1978 in areas formerly dominated by it. Consequently, kelp forests were more extensive in 1998 than they were at the time of reserve creation. Urchin-dominated barrens occupied only 14 % of available reef substratum in reserves as opposed to 40"4 in unprotected areas. These changes in community structure, which have persisted since at least 1994, demonstrate not only higher trophic complexity than anticipated in Australasian ecosystems but also increased primary and secondary productivity in marine reserves as a consequence of protection. Trends inside reserves indicate large-scale reduction of benthic primary production as an indirect result of fishing activity in unprotected areas.

BACKGROUND & AIMS: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress, and novel therapeutic response in PC to develop a biomarker-driven therapeutic strategy targeting DDR and replication stress in PC. METHODS: We interrogated the transcriptome, genome, proteome, and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient-derived xenografts and human PC organoids. RESULTS: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors, including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, cosegregates with response to platinum (P < .001) and PARP inhibitor therapy (P < .001) in vitro and in vivo. We generated a novel signature of replication stress that predicts response to ATR (P < .018) and WEE1 inhibitor (P < .029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < .001) but was not associated with DDR deficiency. CONCLUSIONS: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy.

Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3β) a key regulator of glycolysis. Pharmacological inhibition of GSK3β results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3β inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC.