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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    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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    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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    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.