Centre for Cancer Research - Research Publications

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    ROR1 and ROR2 expression in pancreatic cancer
    Liu, D ; Sharbeen, G ; Phillips, P ; Ford, CE (BMC, 2021-11-11)
    BACKGROUND: The Wnt receptors ROR1 and ROR2 are generating increased interest as cancer therapeutic targets but remain understudied in pancreatic ductal adenocarcinoma (PDAC). Compared to canonical Wnt/ β-catenin signalling, the role of noncanonical Wnt signalling in PDAC remains largely unknown. Only one study has investigated the prognostic significance of the noncanonical Wnt signalling receptor, ROR2 in PDAC. No studies have investigated the prognostic role of ROR1 in PDAC. METHODS: Here, we performed analysis of ROR1 and ROR2 mRNA expression in three publicly available datasets ICGC-PACA-AU (n = 81), TCGA-PAAD (n = 150) and CPTAC-PDAC (n = 137). ROR1 and ROR2 protein expression from the CPTAC-PDAC discovery cohort were also analysed. Immunohistochemistry (IHC) using the validated anti ROR1 monoclonal antibody (4A5) was performed on the Australian Pancreatic Cancer Genome Initiative (APGI) cohort of PDAC samples (n = 152). Association between ROR1 cytoplasmic staining intensity and clinicopathological parameters including stage, grade and overall survival (OS) was investigated. RESULTS: High ROR1 mRNA expression levels correlated with a favourable OS outcome in all of the ICGC-PACA-AU, TCGA-PAAD and CPTAC-PDAC cohorts. ROR1 protein expression was not associated with stage, grade or OS in the APGI cohort. CONCLUSION: ROR1 and ROR2 have potential as prognostic markers when measured at the mRNA level in PDAC. Our IHC cohort did not support ROR1 protein expression in predicting OS, and highlighted the discrepancy of prognostic biomarkers when measured by MS, IHC and RNAseq.
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    Genomic and Molecular Analyses Identify Molecular Subtypes of Pancreatic Cancer Recurrence
    Dreyer, SB ; Upstill-Goddard, R ; Legrini, A ; Biankin, AV ; Jamieson, NB ; Chang, DK ; Allison, S ; Biankin, AV ; Beraldi, D ; Cameron, E ; Chang, DK (W B SAUNDERS CO-ELSEVIER INC, 2022-01)
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    Inhibition of Group 1 p21-Activated Kinases Suppresses Pancreatic Stellate Cell Activation and Increases Survival of Mice with Pancreatic Cancer
    Yeo, D ; Phillips, P ; Baldwin, GS ; He, H ; Nikfarjam, M (WILEY, 2017-05-01)
    Pancreatic cancer remains one of the most lethal of all solid tumors. Pancreatic stellate cells (PSCs) are primarily responsible for the fibrosis that constitutes the stroma and p21-activated kinase 1 (PAK1) may have a role in signalling pathways involving PSCs. This study aimed to examine the role of PAK1 in PSCs and in the interaction of PSCs with pancreatic cancer cells. Human PSCs were isolated using the modified outgrowth method. The effect of inhibiting PAK1 with group 1 PAK inhibitor, FRAX597, on cell proliferation and apoptosis in vitro was measured by thymidine incorporation and annexin V assays, respectively. The effect of depleting host PAK1 on the survival of mice with pancreatic Pan02 cell tumors was evaluated using PAK1 knockout (KO) mice. PAK1 was expressed in isolated PSCs. FRAX597 reduced the activation of PSCs, inhibited PSC proliferation, and increased PSC apoptosis at least in partial by inhibiting PAK1 activity. The decreased expression and activity of PAK1 in PAK1 KO mice tumors was associated with an increased mouse survival. These results implicate PAK1 as a regulator of PSC activation, proliferation and apoptosis. Targeting stromal PAK1 could increase therapeutic response and survival of patients with pancreatic cancer.
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    Targeting the undruggable in pancreatic cancer using nano-based gene silencing drugs.
    Kokkinos, J ; Ignacio, RMC ; Sharbeen, G ; Boyer, C ; Gonzales-Aloy, E ; Goldstein, D ; Australian Pancreatic Cancer Genome Initiative Apgi, ; McCarroll, JA ; Phillips, PA (Elsevier BV, 2020-05)
    Pancreatic cancer is predicted to be the second leading cause of cancer-related death by 2025. The best chemotherapy only extends survival by an average of 18 weeks. The extensive fibrotic stroma surrounding the tumor curbs therapeutic options as chemotherapy drugs cannot freely penetrate the tumor. RNA interference (RNAi) has emerged as a promising approach to revolutionize cancer treatment. Small interfering RNA (siRNA) can be designed to inhibit the expression of any gene which is important given the high degree of genetic heterogeneity present in pancreatic tumors. Despite the potential of siRNA therapies, there are hurdles limiting their clinical application such as poor transport across biological barriers, limited cellular uptake, degradation, and rapid clearance. Nanotechnology can address these challenges. In fact, the past few decades have seen the conceptualization, design, pre-clinical testing and recent clinical approval of a RNAi nanodrug to treat disease. In this review, we comment on the current state of play of clinical trials evaluating siRNA nanodrugs and review pre-clinical studies investigating the efficacy of siRNA therapeutics in pancreatic cancer. We assess the physiological barriers unique to pancreatic cancer that need to be considered when designing and testing new nanomedicines for this disease.
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    Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer
    Dreyer, SB ; Upstill-Goddard, R ; Paulus-Hock, V ; Paris, C ; Lampraki, E-M ; Dray, E ; Serrels, B ; Caligiuri, G ; Rebus, S ; Plenker, D ; Galluzzo, Z ; Brunton, H ; Cunningham, R ; Tesson, M ; Nourse, C ; Bailey, U-M ; Jones, M ; Moran-Jones, K ; Wright, DW ; Duthie, F ; Oien, K ; Evers, L ; McKay, CJ ; McGregor, GA ; Gulati, A ; Brough, R ; Bajrami, I ; Pettitt, S ; Dziubinski, ML ; Candido, J ; Balkwill, F ; Barry, ST ; Grutzmann, R ; Rahib, L ; Johns, A ; Pajic, M ; Froeling, FEM ; Beer, P ; Musgrove, EA ; Petersen, GM ; Ashworth, A ; Frame, MC ; Crawford, HC ; Simeone, DM ; Lord, C ; Mukhopadhyay, D ; Pilarsky, C ; Tuveson, DA ; Cooke, SL ; Jamieson, NB ; Morton, JP ; Sansom, OJ ; Bailey, PJ ; Biankin, A ; Chang, DK (W B SAUNDERS CO-ELSEVIER INC, 2021-01)
    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.
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    DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association
    Lakis, V ; Lawlor, RT ; Newell, F ; Patch, A-M ; Mafficini, A ; Sadanandam, A ; Koufariotis, LT ; Johnston, RL ; Leonard, C ; Wood, S ; Rusev, B ; Corbo, V ; Luchini, C ; Cingarlini, S ; Landoni, L ; Salvia, R ; Milella, M ; Chang, D ; Bailey, P ; Jamieson, NB ; Duthie, F ; Gingras, M-C ; Muzny, DM ; Wheeler, DA ; Gibbs, RA ; Milione, M ; Pederzoli, P ; Samra, JS ; Gill, AJ ; Johns, AL ; Pearson, J ; Biankin, A ; Grimmond, SM ; Waddell, N ; Nones, K ; Scarpa, A (NATURE PORTFOLIO, 2021-02-03)
    Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.
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    The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma
    Perez-Mancera, PA ; Rust, AG ; van der Weyden, L ; Kristiansen, G ; Li, A ; Sarver, AL ; Silverstein, KAT ; Gruetzmann, R ; Aust, D ; Ruemmele, P ; Knoesel, T ; Herd, C ; Stemple, DL ; Kettleborough, R ; Brosnan, JA ; Li, A ; Morgan, R ; Knight, S ; Yu, J ; Stegeman, S ; Collier, LS ; ten Hoeve, JJ ; de Ridder, J ; Klein, AP ; Goggins, M ; Hruban, RH ; Chang, DK ; Biankin, AV ; Grimmond, SM ; Wessels, LFA ; Wood, SA ; Iacobuzio-Donahue, CA ; Pilarsky, C ; Largaespada, DA ; Adams, DJ ; Tuveson, DA (NATURE PUBLISHING GROUP, 2012-06-14)
    Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations in addition to numerous lower frequency genetic events of uncertain significance. Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis in a mouse model of pancreatic ductal preneoplasia to identify genes that cooperate with oncogenic Kras(G12D) to accelerate tumorigenesis and promote progression. Our screen revealed new candidate genes for PDA and confirmed the importance of many genes and pathways previously implicated in human PDA. The most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumours. Although previous work had attributed a pro-survival role to USP9X in human neoplasia, we found instead that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis. Clinically, low USP9X protein and messenger RNA expression in PDA correlates with poor survival after surgery, and USP9X levels are inversely associated with metastatic burden in advanced disease. Furthermore, chromatin modulation with trichostatin A or 5-aza-2'-deoxycytidine elevates USP9X expression in human PDA cell lines, indicating a clinical approach for certain patients. The conditional deletion of Usp9x cooperated with Kras(G12D) to accelerate pancreatic tumorigenesis in mice, validating their genetic interaction. We propose that USP9X is a major tumour suppressor gene with prognostic and therapeutic relevance in PDA.
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    RON is not a prognostic marker for resectable pancreatic cancer
    Tactacan, CM ; Chang, DK ; Cowley, MJ ; Humphrey, ES ; Wu, J ; Gill, AJ ; Chou, A ; Nones, K ; Grimmond, SM ; Sutherland, RL ; Biankin, AV ; Daly, RJ (BMC, 2012-09-07)
    BACKGROUND: The receptor tyrosine kinase RON exhibits increased expression during pancreatic cancer progression and promotes migration, invasion and gemcitabine resistance of pancreatic cancer cells in experimental models. However, the prognostic significance of RON expression in pancreatic cancer is unknown. METHODS: RON expression was characterized in several large cohorts, including a prospective study, totaling 492 pancreatic cancer patients and relationships with patient outcome and clinico-pathologic variables were assessed. RESULTS: RON expression was associated with outcome in a training set, but this was not recapitulated in the validation set, nor was there any association with therapeutic responsiveness in the validation set or the prospective study. CONCLUSIONS: Although RON is implicated in pancreatic cancer progression in experimental models, and may constitute a therapeutic target, RON expression is not associated with prognosis or therapeutic responsiveness in resected pancreatic cancer.
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    HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer
    Brunton, H ; Caligiuri, G ; Cunningham, R ; Upstill-Goddard, R ; Bailey, U-M ; Garner, IM ; Nourse, C ; Dreyer, S ; Jones, M ; Moran-Jones, K ; Wright, DW ; Paulus-Hock, V ; Nixon, C ; Thomson, G ; Jamieson, NB ; McGregor, GA ; Evers, L ; McKay, CJ ; Gulati, A ; Brough, R ; Bajrami, I ; Pettitt, SJ ; Dziubinski, ML ; Barry, ST ; Gruetzmann, R ; Brown, R ; Curry, E ; Pajic, M ; Musgrove, EA ; Petersen, GM ; Shanks, E ; Ashworth, A ; Crawford, HC ; Simeone, DM ; Froeling, FEM ; Lord, CJ ; Mukhopadhyay, D ; Pilarsky, C ; Grimmond, SE ; Morton, JP ; Sansom, OJ ; Chang, DK ; Bailey, PJ ; Biankin, A (CELL PRESS, 2020-05-12)
    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.
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    CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan
    Vennin, C ; Melenec, P ; Rouet, R ; Nobis, M ; Cazet, AS ; Murphy, KJ ; Herrmann, D ; Reed, DA ; Lucas, MC ; Warren, SC ; Elgundi, Z ; Pinese, M ; Kalna, G ; Roden, D ; Samuel, M ; Zaratzian, A ; Grey, ST ; Da Silva, A ; Leung, W ; Mathivanan, S ; Wang, Y ; Braithwaite, AW ; Christ, D ; Benda, A ; Parkin, A ; Phillips, PA ; Whitelock, JM ; Gill, AJ ; Sansom, OJ ; Croucher, DR ; Parker, BL ; Pajic, M ; Morton, JP ; Cox, TR ; Timpson, P ; Johns, AL ; Chantrill, LA ; Chou, A ; Steinmann, A ; Arshi, M ; Dwarte, T ; Froio, D ; Pereira, B ; Ritchie, S ; Chambers, CR ; Metcalf, X ; Waddell, N ; Pearson, J ; Patch, A-M ; Nones, K ; Newell, F ; Mukhopadhyay, P ; Addala, V ; Kazakoff, S ; Holmes, O ; Leonard, C ; Wood, S ; Grimmond, SM ; Hofmann, O ; Christ, A ; Bruxner, T ; Samra, JS ; Pavlakis, N ; High, HA ; Asghari, R ; Merrett, ND ; Pavey, D ; Das, A ; Cosman, PH ; Ismail, K ; O'Connnor, C ; Stoita, A ; Williams, D ; Spigellman, A ; Lam, VW ; McLeod, D ; Kirk, J ; Kench, JG ; Grimison, P ; Cooper, CL ; Sandroussi, C ; Goodwin, A ; Mead, RS ; Tucker, K ; Andrews, L ; Texler, M ; Forest, C ; Epari, KP ; Ballal, M ; Fletcher, DR ; Mukhedkar, S ; Zeps, N ; Beilin, M ; Feeney, K ; Nguyen, NQ ; Ruszkiewicz, AR ; Worthley, C ; Chen, J ; Brooke-Smith, ME ; Papangelis, V ; Clouston, AD ; Barbour, AP ; O'Rourke, TJ ; Fawcett, JW ; Slater, K ; Hatzifotis, M ; Hodgkinson, P ; Nikfarjam, M ; Eshleman, JR ; Hruban, RH ; Wolfgang, CL ; Lawlor, RT ; Beghelli, S ; Corbo, V ; Scardoni, M ; Bassi, C ; Biankin, A ; Dixon, J ; Jamieson, NB ; Chang, DK (NATURE PORTFOLIO, 2019-08-12)
    Heterogeneous subtypes of cancer-associated fibroblasts (CAFs) coexist within pancreatic cancer tissues and can both promote and restrain disease progression. Here, we interrogate how cancer cells harboring distinct alterations in p53 manipulate CAFs. We reveal the existence of a p53-driven hierarchy, where cancer cells with a gain-of-function (GOF) mutant p53 educate a dominant population of CAFs that establish a pro-metastatic environment for GOF and null p53 cancer cells alike. We also demonstrate that CAFs educated by null p53 cancer cells may be reprogrammed by either GOF mutant p53 cells or their CAFs. We identify perlecan as a key component of this pro-metastatic environment. Using intravital imaging, we observe that these dominant CAFs delay cancer cell response to chemotherapy. Lastly, we reveal that depleting perlecan in the stroma combined with chemotherapy prolongs mouse survival, supporting it as a potential target for anti-stromal therapies in pancreatic cancer.