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1. CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan

Author

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, Yx, 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, Jv, Patch, Am, 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, Av, Dixon, J, Jamieson, Nb, and Chang, Dk

Subjects
0301 basic medicine, medicine.medical_treatment, Drug Resistance, General Physics and Astronomy, 02 engineering and technology, Mice, Cancer-Associated Fibroblasts, Cell Movement, lcsh:Science, Inbred BALB C, Cancer, education.field_of_study, Mice, Inbred BALB C, Multidisciplinary, Tumor, 021001 nanoscience & nanotechnology, 3. Good health, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, 0210 nano-technology, Pancreas, Signal Transduction, Cancer microenvironment, Cell biology, Science, Population, Perlecan, Biology, General Biochemistry, Genetics and Molecular Biology, Article, Cell Line, 03 medical and health sciences, Pancreatic cancer, Cell Line, Tumor, medicine, Humans, Animals, Neoplasm Invasiveness, education, Cell Proliferation, Neoplastic, fungi, General Chemistry, Immunotherapy, medicine.disease, Pancreatic Neoplasms, 030104 developmental biology, Gene Expression Regulation, Drug Resistance, Neoplasm, Cancer cell, Cancer research, biology.protein, Neoplasm, lcsh:Q, Stromal Cells, Tumor Suppressor Protein p53, Heparan Sulfate Proteoglycans
Abstract

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., Subtypes of cancer associated fibroblasts can both promote and suppress tumorigenesis. Here, the authors investigate how p53 status in pancreatic cancer cells affects their interaction with cancer associated fibroblasts, and report perlecan as a mediator of the pro-metastatic environment.

Published
2019

2. DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association

Author

Lakis, V, Lawlor, RT, Newell, F, Patch, AM, 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, MC, Muzny, DM, Wheeler, DA, Gibbs, RA, Milione, M, Chantrill, LA, Timpson, P, Chou, A, Pajic, M, Murphy, A, Dwarte, T, Hermann, D, Vennin, C, Cox, TR, Pereira, B, Ritchie, S, Reed, DA, Chambers, CR, Metcalf, X, Nobis, M, Mukhopadhyay, P, Addala, V, Kazakoff, S, Holmes, O, Xu, Q, Hofmann, O, Samra, JS, Pavlakis, N, Arena, J, 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, Sandroussi, C, Goodwin, A, Mead, RS, Tucker, K, Andrews, L, Texler, M, Forest, C, Ballal, M, Fletcher, DR, Zeps, N, 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, Dixon, J, Scardoni, M, Bassi, C, Grimaldi, S, Cantù, C, Bonizzato, G, Bersani, S, Lakis, V, Lawlor, RT, Newell, F, Patch, AM, 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, MC, Muzny, DM, Wheeler, DA, Gibbs, RA, Milione, M, Chantrill, LA, Timpson, P, Chou, A, Pajic, M, Murphy, A, Dwarte, T, Hermann, D, Vennin, C, Cox, TR, Pereira, B, Ritchie, S, Reed, DA, Chambers, CR, Metcalf, X, Nobis, M, Mukhopadhyay, P, Addala, V, Kazakoff, S, Holmes, O, Xu, Q, Hofmann, O, Samra, JS, Pavlakis, N, Arena, J, 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, Sandroussi, C, Goodwin, A, Mead, RS, Tucker, K, Andrews, L, Texler, M, Forest, C, Ballal, M, Fletcher, DR, Zeps, N, 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, Dixon, J, Scardoni, M, Bassi, C, Grimaldi, S, Cantù, C, Bonizzato, G, and Bersani, S

Abstract

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.

Published
2021

3. Lost in translation: Returning germline genetic results in genome-scale cancer research

Author

Johns, AL, McKay, SH, Humphris, JL, Pinese, M, Chantrill, LA, Mead, RS, Tucker, K, Andrews, L, Goodwin, A, Leonard, C, High, HA, Nones, K, Waddell, N, Patch, AM, Merrett, ND, Pavlakis, N, Kassahn, KS, Samra, JS, Miller, DK, Chang, DK, Pajic, M, Pearson, JV, Grimmond, SM, Zeps, N, Gill, AJ, Biankin, AV, Chin, VT, Chou, A, Steinmann, A, Arshi, M, Drury, A, Froio, D, Morgan, A, Timpson, P, Hermann, D, Vennin, C, Warren, S, Wu, J, Pinho, AV, Newell, F, Mukhopadhyay, P, Addala, V, Kazakoff, S, Holmes, O, Wood, S, Xu, C, Hofmann, O, Wilson, PJ, Christ, A, Bruxner, T, Samra, S, Arena, J, Mittal, A, Asghari, R, Pavey, D, Das, A, Cosman, PH, Ismail, K, O'Connnor, C, Williams, D, Spigellman, A, Lam, W, McLeod, D, Nagrial, AM, Kirk, J, James, V, Grimison, P, Cooper, CL, Sandroussi, C, Forest, C, Epari, KP, Ballal, M, Fletcher, DR, Mukhedkar, S, Beilin, M, Feeney, K, Nguyen, NQ, Ruszkiewicz, AR, Worthley, C, Brooke-Smith, ME, Papangelis, V, Clouston, AD, Martin, P, Barbour, AP, O'Rourke, TJ, Fawcett, JW, Slater, K, Hatzifotis, M, Hodgkinson, P, Hruban, RH, Wolfgang, CL, Hodgin, M, Lawlor, RT, Beghelli, S, Corbo, V, Scardoni, M, Bassi, C, Bailey, P, Martin, S, Musgrove, EA, Johns, AL, McKay, SH, Humphris, JL, Pinese, M, Chantrill, LA, Mead, RS, Tucker, K, Andrews, L, Goodwin, A, Leonard, C, High, HA, Nones, K, Waddell, N, Patch, AM, Merrett, ND, Pavlakis, N, Kassahn, KS, Samra, JS, Miller, DK, Chang, DK, Pajic, M, Pearson, JV, Grimmond, SM, Zeps, N, Gill, AJ, Biankin, AV, Chin, VT, Chou, A, Steinmann, A, Arshi, M, Drury, A, Froio, D, Morgan, A, Timpson, P, Hermann, D, Vennin, C, Warren, S, Wu, J, Pinho, AV, Newell, F, Mukhopadhyay, P, Addala, V, Kazakoff, S, Holmes, O, Wood, S, Xu, C, Hofmann, O, Wilson, PJ, Christ, A, Bruxner, T, Samra, S, Arena, J, Mittal, A, Asghari, R, Pavey, D, Das, A, Cosman, PH, Ismail, K, O'Connnor, C, Williams, D, Spigellman, A, Lam, W, McLeod, D, Nagrial, AM, Kirk, J, James, V, Grimison, P, Cooper, CL, Sandroussi, C, Forest, C, Epari, KP, Ballal, M, Fletcher, DR, Mukhedkar, S, Beilin, M, Feeney, K, Nguyen, NQ, Ruszkiewicz, AR, Worthley, C, Brooke-Smith, ME, Papangelis, V, Clouston, AD, Martin, P, Barbour, AP, O'Rourke, TJ, Fawcett, JW, Slater, K, Hatzifotis, M, Hodgkinson, P, Hruban, RH, Wolfgang, CL, Hodgin, M, Lawlor, RT, Beghelli, S, Corbo, V, Scardoni, M, Bassi, C, Bailey, P, Martin, S, and Musgrove, EA

Abstract

Background: The return of research results (RoR) remains a complex and well-debated issue. Despite the debate, actual data related to the experience of giving individual results back, and the impact these results may have on clinical care and health outcomes, is sorely lacking. Through the work of the Australian Pancreatic Cancer Genome Initiative (APGI) we: (1) delineate the pathway back to the patient where actionable research data were identified; and (2) report the clinical utilisation of individual results returned. Using this experience, we discuss barriers and opportunities associated with a comprehensive process of RoR in large-scale genomic research that may be useful for others developing their own policies. Methods: We performed whole-genome (n = 184) and exome (n = 208) sequencing of matched tumour-normal DNA pairs from 392 patients with sporadic pancreatic cancer (PC) as part of the APGI. We identified pathogenic germline mutations in candidate genes (n = 130) with established predisposition to PC or medium-high penetrance genes with well-defined cancer associated syndromes or phenotypes. Variants from candidate genes were annotated and classified according to international guidelines. Variants were considered actionable if clinical utility was established, with regard to prevention, diagnosis, prognostication and/or therapy. Results: A total of 48,904 germline variants were identified, with 2356 unique variants undergoing annotation and in silico classification. Twenty cases were deemed actionable and were returned via previously described RoR framework, representing an actionable finding rate of 5.1%. Overall, 1.78% of our cohort experienced clinical benefit from RoR. Conclusion: Returning research results within the context of large-scale genomics research is a labour-intensive, highly variable, complex operation. Results that warrant action are not infrequent, but the prevalence of those who experience a clinical difference as a result of returning

Published
2017

4. Lost in translation: returning germline genetic results in genome-scale cancer research.

Author

Johns AL, McKay SH, Humphris JL, Pinese M, Chantrill LA, Mead RS, Tucker K, Andrews L, Goodwin A, Leonard C, High HA, Nones K, Patch AM, Merrett ND, Pavlakis N, Kassahn KS, Samra JS, Miller DK, Chang DK, Pajic M, Pearson JV, Grimmond SM, Waddell N, Zeps N, Gill AJ, and Biankin AV

Subjects
Adult, Aged, Aged, 80 and over, Australia, Computer Simulation, DNA Mutational Analysis, Genomics, Humans, Middle Aged, Genetic Predisposition to Disease, Genome, Human, Germ-Line Mutation, Pancreatic Neoplasms genetics
Abstract

Background: The return of research results (RoR) remains a complex and well-debated issue. Despite the debate, actual data related to the experience of giving individual results back, and the impact these results may have on clinical care and health outcomes, is sorely lacking. Through the work of the Australian Pancreatic Cancer Genome Initiative (APGI) we: (1) delineate the pathway back to the patient where actionable research data were identified; and (2) report the clinical utilisation of individual results returned. Using this experience, we discuss barriers and opportunities associated with a comprehensive process of RoR in large-scale genomic research that may be useful for others developing their own policies., Methods: We performed whole-genome (n = 184) and exome (n = 208) sequencing of matched tumour-normal DNA pairs from 392 patients with sporadic pancreatic cancer (PC) as part of the APGI. We identified pathogenic germline mutations in candidate genes (n = 130) with established predisposition to PC or medium-high penetrance genes with well-defined cancer associated syndromes or phenotypes. Variants from candidate genes were annotated and classified according to international guidelines. Variants were considered actionable if clinical utility was established, with regard to prevention, diagnosis, prognostication and/or therapy., Results: A total of 48,904 germline variants were identified, with 2356 unique variants undergoing annotation and in silico classification. Twenty cases were deemed actionable and were returned via previously described RoR framework, representing an actionable finding rate of 5.1%. Overall, 1.78% of our cohort experienced clinical benefit from RoR., Conclusion: Returning research results within the context of large-scale genomics research is a labour-intensive, highly variable, complex operation. Results that warrant action are not infrequent, but the prevalence of those who experience a clinical difference as a result of returning individual results is currently low.

Published
2017
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5. Safety and efficacy of nandrolone decanoate for treatment of wasting in patients with HIV infection.

Author

Gold J, High HA, Li Y, Michelmore H, Bodsworth NJ, Finlayson R, Furner VL, Allen BJ, and Oliver CJ

Subjects
Adult, Anthropometry, Body Mass Index, Body Weight drug effects, CD4 Lymphocyte Count, Dietary Fats metabolism, Humans, Male, Middle Aged, Nandrolone adverse effects, Nandrolone therapeutic use, Nandrolone Decanoate, Nitrogen metabolism, Quality of Life, Surveys and Questionnaires, Acquired Immunodeficiency Syndrome complications, Acquired Immunodeficiency Syndrome drug therapy, HIV Infections complications, HIV Infections drug therapy, HIV Wasting Syndrome drug therapy, Nandrolone analogs & derivatives
Abstract

Objective: To evaluate the safety and efficacy of the anabolic steroid, nandrolone decanoate (Deca Durabolin) in patients with HIV wasting who are resistant to nutritional intervention., Design: A 16-week open trial with subjects who had lost 5-15% of their usual body weight., Setting: HIV/AIDS specialist ambulatory care services, both public and private, in sydney, Australia., Participants: Two hundred and twenty men entered the pre-therapy phase, and of these, 24 failed to gain weight and were enrolled. Seventeen subjects (81%) completed the 16-week trial., Interventions: Pre-therapy nutritional assessment and education was conducted by the clinical dietitian. Those who failed to gain weight (10.9%) were treated with nandrolone decanoate (100 mg/ml) by deep intramuscular injection every 2 weeks for 16 weeks., Main Outcome Measures: Changes in weight and body composition (lean body mass, total body water and nitrogen index) were measured by anthropometry, bioelectrical impedance, and in vivo neutron activation. Changes in quality of life were assessed by the 30-item Medical Outcomes Study short form questionnaire. Changes in biochemistry, haematology and immunology were also measured., Results: There were significant increases in weight (mean, 0.14 kg per week; P < 0.05) and lean body mass (mean, 3 kg by anthropometry; P < 0.005). The change in lean body mass was of similar magnitude across all measurement modalities. Quality of life parameters, especially functionality, increased significantly during the trial. No subject experienced toxicity., Conclusion: Nandrolone decanoate has beneficial effects on weight, lean body mass and quality of life in selected patients who have mild to moderate HIV wasting.

Published
1996
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