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1. A RAC-GEF network critical for early intestinal tumourigenesis

Author

Pickering, K. A., Gilroy, K., Cassidy, J. W., Fey, S. K., Najumudeen, A. K., Zeiger, L. B., Vincent, D. F., Gay, D. M., Johansson, J., Fordham, R. P., Miller, B., Clark, W., Hedley, A., Unal, E. B., Kiel, C., McGhee, E., Machesky, L. M., Nixon, C., Johnsson, A. E., Bain, M., Strathdee, D., van Hoof, S. R., Medema, J. P., Anderson, K. I., Brachmann, S. M., Stucke, V. M., Malliri, A., Drysdale, M., Turner, M., Serrano, L., Myant, K., Campbell, A. D., and Sansom, O. J.

Published
2021
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14. Cancer associated fibroblasts in pancreatic ductal adenocarcinoma determine response to SLC7A11 inhibition

Author

Erkan, Murat Mert (ORCID 0000-0002-2753-0234 & YÖK ID 214689), Sharbeen, G.; McCarroll, J. A.; Akerman, A.; Kopecky, C.; Youkhana, J.; Kokkinos, J.; Holst, J.; Boyer, C.; Goldstein, D.; Timpson, P.; Cox, T. R.; Pereira, B. A.; Chitty, J. L.; Fey, S. K.; Najumudeen, A. K.; Campbell, A. D.; Sansom, O. J.; Ignacio, R. M. C.; Naim, S.; Liu, J.; Russia, N.; Lee, J.; Chou, A.; Johns, A.; Gill, A. J.; Gonzales-Aloy, E.; Gebski, V.; Guan, Y. F.; Pajic, M.; Turner, N.; Apte, M. V.; Davis, T. P.; Morton, J. P.; Haghighi, K. S.; Kasparian, J.; McLean, B. J.; Setargew, Y. F. I.; Apgi APCGI; Phillips, P. A., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Erkan, Murat Mert (ORCID 0000-0002-2753-0234 & YÖK ID 214689), Sharbeen, G.; McCarroll, J. A.; Akerman, A.; Kopecky, C.; Youkhana, J.; Kokkinos, J.; Holst, J.; Boyer, C.; Goldstein, D.; Timpson, P.; Cox, T. R.; Pereira, B. A.; Chitty, J. L.; Fey, S. K.; Najumudeen, A. K.; Campbell, A. D.; Sansom, O. J.; Ignacio, R. M. C.; Naim, S.; Liu, J.; Russia, N.; Lee, J.; Chou, A.; Johns, A.; Gill, A. J.; Gonzales-Aloy, E.; Gebski, V.; Guan, Y. F.; Pajic, M.; Turner, N.; Apte, M. V.; Davis, T. P.; Morton, J. P.; Haghighi, K. S.; Kasparian, J.; McLean, B. J.; Setargew, Y. F. I.; Apgi APCGI; Phillips, P. A., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine

Abstract

Cancer-associated fibroblasts (CAF) are major contributors to pancreatic ductal adenocarcinoma (PDAC) progression through protumor signaling and the generation of fibrosis, the latter of which creates a physical barrier to drugs. CAF inhibition is thus an ideal component of any therapeutic approach for PDAC. SLC7A11 is a cystine transporter that has been identified as a potential therapeutic target in PDAC cells. However, no prior study has evaluated the role of SLC7A11 in PDAC tumor stroma and its prognostic significance. Here we show that high expression of SLC7A11 in human PDAC tumor stroma, but not tumor cells, is independently prognostic of poorer overall survival. Orthogonal approaches showed that PDAC-derived CAFs are highly dependent on SLC7A11 for cystine uptake and glutathione synthesis and that SLC7A11 inhibition significantly decreases CAF proliferation, reduces their resistance to oxidative stress, and inhibits their ability to remodel collagen and support PDAC cell growth. Importantly, specific ablation of SLC7A11 from the tumor compartment of transgenic mouse PDAC tumors did not affect tumor growth, suggesting the stroma can substantially influence PDAC tumor response to SLC7A11 inhibition. In a mouse orthotopic PDAC model utilizing human PDAC cells and CAFs, stable knockdown of SLC7A11 was required in both cell types to reduce tumor growth, metastatic spread, and intratumoral fibrosis, demonstrating the importance of targeting SLC7A11 in both compartments. Finally, treatment with a nanoparticle genesilencing drug against SLC7A11, developed by our laboratory, reduced PDAC tumor growth, incidence of metastases, CAF activation, and fibrosis in orthotopic PDAC tumors. Overall, these findings identify an important role of SLC7A11 in PDAC-derived CAFs in supporting tumor growth. Significance: this study demonstrates that SLC7A11 in PDAC stromal cells is important for the tumor-promoting activity of CAFs and validates a clinically translatable nanomedicine, NHMRC Project Grant; Avner Innovation Grant; NHMRC CDF-I; NHMRC Ideas Grant ; Cancer-Institute NSW ECF/CDFs ; Cancer Institute NSW Innovation Grant; Cancer Institute NSW The Professor Rob Sutherland AO Make a Difference Award; Cancer Australia/Cancer Council; Cancer Australia/Kids Cancer Project; Cure Cancer Australia; Tour de Cure PhD Support Scholarship; Tour de Cure Established Research Grant; Tour de Cure Pioneering Research Grant; UNSW Interlude Grant Scheme; Cancer Research UK Core Funding and Grand Challenge Grants; NHMRC CDF-II; NHMRC Senior Research Fellowship; Suttons, Cancer Council NSW; Avner Grant from PanKind; Australian Pancreatic Cancer Foundation; Translational Cancer Research Network and Australian Postgraduate Award Scholarships; Australian Government Research Training Program Scholarship; UNSW Sydney Scientia PhD Scholarship; Pancreatic Cancer UK Future Leaders Academy; Len Ainsworth Pancreatic Cancer Fellowship

Published
2021

21. Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D

Author

Kennedy, S. A., Jarboui, M. -A, Srihari, S., Raso, C., Bryan, K., Dernayka, L., Charitou, T., Bernal-Llinares, M., Herrera-Montavez, C., Krstic, A., Matallanas, D., Kotlyar, M., Jurisica, I., Curak, J., Wong, V., Stagljar, I., LeBihan, T., Imrie, L., Pillai, P., Lynn, M. A., Fasterius, Erik, Al-Khalili Szigyarto, Cristina, Breen, J., Kiel, C., Serrano, L., Rauch, N., Rukhlenko, O., Kholodenko, B. N., Iglesias-Martinez, L. F., Ryan, C. J., Pilkington, R., Cammareri, P., Sansom, O., Shave, S., Auer, M., Horn, N., Klose, F., Ueffing, M., Boldt, K., Lynn, D. J., Kolch, W., Kennedy, S. A., Jarboui, M. -A, Srihari, S., Raso, C., Bryan, K., Dernayka, L., Charitou, T., Bernal-Llinares, M., Herrera-Montavez, C., Krstic, A., Matallanas, D., Kotlyar, M., Jurisica, I., Curak, J., Wong, V., Stagljar, I., LeBihan, T., Imrie, L., Pillai, P., Lynn, M. A., Fasterius, Erik, Al-Khalili Szigyarto, Cristina, Breen, J., Kiel, C., Serrano, L., Rauch, N., Rukhlenko, O., Kholodenko, B. N., Iglesias-Martinez, L. F., Ryan, C. J., Pilkington, R., Cammareri, P., Sansom, O., Shave, S., Auer, M., Horn, N., Klose, F., Ueffing, M., Boldt, K., Lynn, D. J., and Kolch, W.

Abstract

Protein-protein-interaction networks (PPINs) organize fundamental biological processes, but how oncogenic mutations impact these interactions and their functions at a network-level scale is poorly understood. Here, we analyze how a common oncogenic KRAS mutation (KRASG13D) affects PPIN structure and function of the Epidermal Growth Factor Receptor (EGFR) network in colorectal cancer (CRC) cells. Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRASG13D (mtKRAS). The factors driving PPIN rewiring are multifactorial including changes in protein expression and phosphorylation. Mathematical modelling also suggests that the binding dynamics of low and high affinity KRAS interactors contribute to rewiring. PPIN rewiring substantially alters the composition of protein complexes, signal flow, transcriptional regulation, and cellular phenotype. These changes are validated by targeted and global experimental analysis. Importantly, genetic alterations in the most extensively rewired PPIN nodes occur frequently in CRC and are prognostic of poor patient outcomes., QC 20200304

Published
2020
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22. Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D.

Author

Kennedy, SA, Jarboui, M-A, Srihari, S, Raso, C, Bryan, K, Dernayka, L, Charitou, T, Bernal-Llinares, M, Herrera-Montavez, C, Krstic, A, Matallanas, D, Kotlyar, M, Jurisica, I, Curak, J, Wong, V, Stagljar, I, LeBihan, T, Imrie, L, Pillai, P, Lynn, MA, Fasterius, E, Al-Khalili Szigyarto, C, Breen, J, Kiel, C, Serrano, L, Rauch, N, Rukhlenko, O, Kholodenko, BN, Iglesias-Martinez, LF, Ryan, CJ, Pilkington, R, Cammareri, P, Sansom, O, Shave, S, Auer, M, Horn, N, Klose, F, Ueffing, M, Boldt, K, Lynn, DJ, Kolch, W, Kennedy, SA, Jarboui, M-A, Srihari, S, Raso, C, Bryan, K, Dernayka, L, Charitou, T, Bernal-Llinares, M, Herrera-Montavez, C, Krstic, A, Matallanas, D, Kotlyar, M, Jurisica, I, Curak, J, Wong, V, Stagljar, I, LeBihan, T, Imrie, L, Pillai, P, Lynn, MA, Fasterius, E, Al-Khalili Szigyarto, C, Breen, J, Kiel, C, Serrano, L, Rauch, N, Rukhlenko, O, Kholodenko, BN, Iglesias-Martinez, LF, Ryan, CJ, Pilkington, R, Cammareri, P, Sansom, O, Shave, S, Auer, M, Horn, N, Klose, F, Ueffing, M, Boldt, K, Lynn, DJ, and Kolch, W

Abstract

Protein-protein-interaction networks (PPINs) organize fundamental biological processes, but how oncogenic mutations impact these interactions and their functions at a network-level scale is poorly understood. Here, we analyze how a common oncogenic KRAS mutation (KRASG13D) affects PPIN structure and function of the Epidermal Growth Factor Receptor (EGFR) network in colorectal cancer (CRC) cells. Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRASG13D (mtKRAS). The factors driving PPIN rewiring are multifactorial including changes in protein expression and phosphorylation. Mathematical modelling also suggests that the binding dynamics of low and high affinity KRAS interactors contribute to rewiring. PPIN rewiring substantially alters the composition of protein complexes, signal flow, transcriptional regulation, and cellular phenotype. These changes are validated by targeted and global experimental analysis. Importantly, genetic alterations in the most extensively rewired PPIN nodes occur frequently in CRC and are prognostic of poor patient outcomes.

Published
2020

26. Wnt ligands influence tumour initiation by controlling the number of intestinal stem cells

Author

Huels, D. J., primary, Bruens, L., additional, Hodder, M. C., additional, Cammareri, P., additional, Campbell, A. D., additional, Ridgway, R. A., additional, Gay, D. M., additional, Solar-Abboud, M., additional, Faller, W. J., additional, Nixon, C., additional, Zeiger, L. B., additional, McLaughlin, M. E., additional, Morrissey, E., additional, Winton, D. J., additional, Snippert, H. J., additional, van Rheenen, J., additional, and Sansom, O. J., additional

Published
2018
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27. Wnt ligands influence tumour initiation by controlling the number of intestinal stem cells

Author

Huels, D. J., Bruens, L., Hodder, M. C., Cammareri, P., Campbell, A. D., Ridgway, R. A., Gay, D. M., Solar-Abboud, M., Faller, W. J., Nixon, C., Zeiger, L. B., McLaughlin, M. E., Morrissey, E., Winton, D. J., Snippert, H. J., Van Rheenen, J., Sansom, O. J., Huels, D. J., Bruens, L., Hodder, M. C., Cammareri, P., Campbell, A. D., Ridgway, R. A., Gay, D. M., Solar-Abboud, M., Faller, W. J., Nixon, C., Zeiger, L. B., McLaughlin, M. E., Morrissey, E., Winton, D. J., Snippert, H. J., Van Rheenen, J., and Sansom, O. J.

Published
2018

28. Wnt ligands influence tumour initiation by controlling the number of intestinal stem cells

Author

CMM, CMM Groep Snippert, Cancer, CMM Sectie Molecular Cancer Research, Huels, D. J., Bruens, L., Hodder, M. C., Cammareri, P., Campbell, A. D., Ridgway, R. A., Gay, D. M., Solar-Abboud, M., Faller, W. J., Nixon, C., Zeiger, L. B., McLaughlin, M. E., Morrissey, E., Winton, D. J., Snippert, H. J., Van Rheenen, J., Sansom, O. J., CMM, CMM Groep Snippert, Cancer, CMM Sectie Molecular Cancer Research, Huels, D. J., Bruens, L., Hodder, M. C., Cammareri, P., Campbell, A. D., Ridgway, R. A., Gay, D. M., Solar-Abboud, M., Faller, W. J., Nixon, C., Zeiger, L. B., McLaughlin, M. E., Morrissey, E., Winton, D. J., Snippert, H. J., Van Rheenen, J., and Sansom, O. J.

Published
2018

29. Systems biologists seek fuller integration of systems biology approaches in new cancer research programs

Author

Drasdo, D, Fell, D, Ferrell, J, Gallahan, D, Gatenby, R, Guenther, U, Herzel, H, Junghanss, C, Kunz, M, Laplace, F, van Leeuwen, I, Lenormand, P, Levi, F, Linnebacher, M, Lowengrub, J, Maini, P, Marcus, F, Malik, A, Rateitschak, K, Sansom, O, Schafer, R, Schurrle, K, Sers, C, Schnell, S, Harms, B, Shibata, D, Tyson, J, Vera, J, White, M, Zhivotovsky, B, Jaster, R, Wolkenhauer, O, Auffray, C, Baltrusch, S, Bluthgen, N, Byrne, H, Cascante, M, Ciliberto, A, and Dale, T

Abstract

Systems biology takes an interdisciplinary approach to the systematic study of complex interactions in biological systems. This approach seeks to decipher the emergent behaviors of complex systems rather than focusing only on their constituent properties. As an increasing number of examples illustrate the value of systems biology approaches to understand the initiation, progression, and treatment of cancer, systems biologists from across Europe and the United States hope for changes in the way their field is currently perceived among cancer researchers. In a recent EU-US workshop, supported by the European Commission, the German Federal Ministry for Education and Research, and the National Cancer Institute of the NIH, the participants discussed the strengths, weaknesses, hurdles, and opportunities in cancer systems biology.

Published
2016

32. Hypermutation In Pancreatic Cancer

Author

Humphris, J. L., Patch, A. -M., Nones, K., Bailey, P. J., Johns, A. L., Mckay, S., Chang, D. K., Miller, D. K., Pajic, M., Kassahn, K. S., Quinn, M. C. J., Bruxner, T. J. C., Christ, A. N., Harliwong, I., Idrisoglu, S., Manning, S., Nourse, C., Nourbakhsh, E., Stone, A., Wilson, P. J., Anderson, M., Fink, J. L., Holmes, O., Kazakoff, S., Leonard, C., Newell, F., Waddell, N., Wood, S., Mead, R. S., Xu, Q., Wu, J., Pinese, M., Cowley, M. J., Jones, M. D., Nagrial, A. M., Chin, V. T., Chantrill, L. A., Mawson, A., Chou, A., Scarlett, C. J., Pinho, A. V., Rooman, I., Giry-Laterriere, M., Samra, J. S., Kench, J. G., Merrett, N. D., Toon, C. W., Epari, K., Nguyen, N. Q., Barbour, A., Zeps, N., Jamieson, N. B., Mckay, C. J., Carter, C. R., Dickson, E. J., Graham, J. S., Duthie, F., Oien, K., Hair, J., Morton, J. P., Sansom, O. J., Grutzmann, R., Hruban, R. H., Maitra, A., Iacobuzio-Donahue, C. A., Schulick, R. D., Wolfgang, C. L., Morgan, R. A., Lawlor, R. T., Rusev, B., Corbo, V., Salvia, R., Cataldo, I., Tortora, Giampaolo, Tempero, M. A., Hofmann, O., Eshleman, J. R., Pilarsky, C., Scarpa, A., Musgrove, E. A., Gill, A. J., Pearson, J. V., Grimmond, S. M., Biankin, A. V., Tortora G. (ORCID:0000-0002-1378-4962), Humphris, J. L., Patch, A. -M., Nones, K., Bailey, P. J., Johns, A. L., Mckay, S., Chang, D. K., Miller, D. K., Pajic, M., Kassahn, K. S., Quinn, M. C. J., Bruxner, T. J. C., Christ, A. N., Harliwong, I., Idrisoglu, S., Manning, S., Nourse, C., Nourbakhsh, E., Stone, A., Wilson, P. J., Anderson, M., Fink, J. L., Holmes, O., Kazakoff, S., Leonard, C., Newell, F., Waddell, N., Wood, S., Mead, R. S., Xu, Q., Wu, J., Pinese, M., Cowley, M. J., Jones, M. D., Nagrial, A. M., Chin, V. T., Chantrill, L. A., Mawson, A., Chou, A., Scarlett, C. J., Pinho, A. V., Rooman, I., Giry-Laterriere, M., Samra, J. S., Kench, J. G., Merrett, N. D., Toon, C. W., Epari, K., Nguyen, N. Q., Barbour, A., Zeps, N., Jamieson, N. B., Mckay, C. J., Carter, C. R., Dickson, E. J., Graham, J. S., Duthie, F., Oien, K., Hair, J., Morton, J. P., Sansom, O. J., Grutzmann, R., Hruban, R. H., Maitra, A., Iacobuzio-Donahue, C. A., Schulick, R. D., Wolfgang, C. L., Morgan, R. A., Lawlor, R. T., Rusev, B., Corbo, V., Salvia, R., Cataldo, I., Tortora, Giampaolo, Tempero, M. A., Hofmann, O., Eshleman, J. R., Pilarsky, C., Scarpa, A., Musgrove, E. A., Gill, A. J., Pearson, J. V., Grimmond, S. M., Biankin, A. V., and Tortora G. (ORCID:0000-0002-1378-4962)

Abstract

Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.

Published
2017

33. Hypermutation In Pancreatic Cancer

Author

Humphris, J., Patch, A., Nones, K., Bailey, P., Johns, A., Mckay, S., Chang, D., Miller, D., Pajic, M., Kassahn, K., Quinn, M., Bruxner, T., Christ, A., Harliwong, I., Idrisoglu, S., Manning, S., Nourse, C., Nourbakhsh, E., Stone, A., Wilson, P., Anderson, M., Fink, J., Holmes, O., Kazakoff, S., Leonard, C., Newell, F., Waddell, N., Wood, S., Mead, R., Xu, Q., Wu, J., Pinese, M., Cowley, M., Jones, M., Nagrial, A., Chin, V., Chantrill, L., Mawson, A., Chou, A., Scarlett, C., Pinho, A., Rooman, I., Giry-Laterriere, M., Samra, J., Kench, J., Merrett, N., Toon, C., Epari, K., Nguyen, N., Barbour, A., Zeps, Nikolajs, Jamieson, N., McKay, C., Carter, C., Dickson, E., Graham, J., Duthie, F., Oien, K., Hair, J., Morton, J., Sansom, O., Gruetzmann, R., Hruban, R., Maitra, A., Iacobuzio-Donahue, C., Schulick, R., Wolfgang, C., Morgan, R., Lawlor, R., Rusev, B., Corbo, V., Salvia, R., Cataldo, I., Tortora, G., Tempero, M., Hofmann, O., Eshleman, J., Pilarsky, C., Scarpa, A., Musgrove, E., Gill, A., Pearson, J., Grimmond, S., Biankin, A., Humphris, J., Patch, A., Nones, K., Bailey, P., Johns, A., Mckay, S., Chang, D., Miller, D., Pajic, M., Kassahn, K., Quinn, M., Bruxner, T., Christ, A., Harliwong, I., Idrisoglu, S., Manning, S., Nourse, C., Nourbakhsh, E., Stone, A., Wilson, P., Anderson, M., Fink, J., Holmes, O., Kazakoff, S., Leonard, C., Newell, F., Waddell, N., Wood, S., Mead, R., Xu, Q., Wu, J., Pinese, M., Cowley, M., Jones, M., Nagrial, A., Chin, V., Chantrill, L., Mawson, A., Chou, A., Scarlett, C., Pinho, A., Rooman, I., Giry-Laterriere, M., Samra, J., Kench, J., Merrett, N., Toon, C., Epari, K., Nguyen, N., Barbour, A., Zeps, Nikolajs, Jamieson, N., McKay, C., Carter, C., Dickson, E., Graham, J., Duthie, F., Oien, K., Hair, J., Morton, J., Sansom, O., Gruetzmann, R., Hruban, R., Maitra, A., Iacobuzio-Donahue, C., Schulick, R., Wolfgang, C., Morgan, R., Lawlor, R., Rusev, B., Corbo, V., Salvia, R., Cataldo, I., Tortora, G., Tempero, M., Hofmann, O., Eshleman, J., Pilarsky, C., Scarpa, A., Musgrove, E., Gill, A., Pearson, J., Grimmond, S., and Biankin, A.

Abstract

© 2017 AGA Institute Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.

Published
2017

34. Mutations in Apc and p53 Synergize to Promote Mammary Neoplasia

Author

Méniel, V., Hay, T., Douglas-Jones, A., Sansom, O. J., and Alan Clarke

Subjects
Cyclin-Dependent Kinase Inhibitor p21, Metaplasia, Mice, Inbred C3H, Cancer Research, Genes, APC, Adenomatous Polyposis Coli Protein, Mammary Neoplasms, Experimental, Cell Cycle Proteins, Genes, p53, Up-Regulation, Mice, Inbred C57BL, Cytoskeletal Proteins, Mice, Cell Transformation, Neoplastic, Mammary Glands, Animal, Oncology, Pregnancy, Trans-Activators, Animals, Female, Gene Silencing, Tumor Suppressor Protein p53, Frameshift Mutation, beta Catenin
Abstract

Mutations of Apc and p53 have both been implicated in human and murine mammary neoplasia. To investigate potential interactions between Apc and p53, we conditionally inactivated Apc in both the presence and the absence of functional p53. Apc deficiency on its own leads to the development of metaplasia but not neoplasia. We show here that these areas of metaplasia are characterized by elevated levels of both p53 and p21. In the additional absence of p53,there is rapid progression to neoplasia, with 44.4% of lymphoma-free mice developing a mammary tumor with earliest observed onset at pregnancy. To investigate the mechanism by which p53 deficiency accelerates neoplasia, we used the Rosa26R reporter strain as a marker of Cre-mediated recombination and show a role for p53 in the loss of Apc-deficient cells. This role seems limited to pregnancy and subsequent time points. We therefore show clear synergy between these two mutations in mammary gland neoplasia and present data to suggest that at least one mechanism for this acceleration is the p53-dependent loss of Apc-deficient cells.

Published
2005
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36. Genomic analyses identify molecular subtypes of pancreatic cancer

Author

Bailey, P., Chang, D., Nones, K., Johns, A., Patch, A., Gingras, M., Miller, D., Christ, A., Bruxner, T., Quinn, M., Nourse, C., Murtaugh, L., Harliwong, I., Idrisoglu, S., Manning, S., Nourbakhsh, E., Wani, S., Fink, L., Holmes, O., Chin, V., Anderson, M., Kazakoff, S., Leonard, C., Newell, F., Waddell, N., Wood, S., Xu, Q., Wilson, P., Cloonan, N., Kassahn, K., Taylor, D., Quek, K., Robertson, A., Pantano, L., Mincarelli, L., Sanchez, L., Evers, L., Wu, J., Pinese, M., Cowley, M., Jones, M., Colvin, E., Nagrial, A., Humphrey, E., Chantrill, L., Mawson, A., Humphris, J., Chou, A., Pajic, M., Scarlett, C., Pinho, A., Giry-Laterriere, M., Rooman, I., Samra, J., Kench, J., Lovell, J., Merrett, N., Toon, C., Epari, K., Nguyen, N., Barbour, A., Zeps, Nikolajs, Moran-Jones, K., Jamieson, N., Graham, J., Duthie, F., Oien, K., Hair, J., Gruetzmann, R., Maitra, A., Iacobuzio-Donahue, C., Wolfgang, C., Morgan, R., Lawlor, R., Corbo, V., Bassi, C., Rusev, B., Capelli, P., Salvia, R., Tortora, G., Mukhopadhyay, D., Petersen, G., Munzy, D., Fisher, W., Karim, S., Eshleman, J., Hruban, R., Pilarsky, C., Morton, J., Sansom, O., Scarpa, A., Musgrove, E., Bailey, U., Hofmann, O., Sutherland, R., Wheeler, D., Gill, A., Gibbs, R., Pearson, J., Biankin, A., Grimmond, S., Bailey, P., Chang, D., Nones, K., Johns, A., Patch, A., Gingras, M., Miller, D., Christ, A., Bruxner, T., Quinn, M., Nourse, C., Murtaugh, L., Harliwong, I., Idrisoglu, S., Manning, S., Nourbakhsh, E., Wani, S., Fink, L., Holmes, O., Chin, V., Anderson, M., Kazakoff, S., Leonard, C., Newell, F., Waddell, N., Wood, S., Xu, Q., Wilson, P., Cloonan, N., Kassahn, K., Taylor, D., Quek, K., Robertson, A., Pantano, L., Mincarelli, L., Sanchez, L., Evers, L., Wu, J., Pinese, M., Cowley, M., Jones, M., Colvin, E., Nagrial, A., Humphrey, E., Chantrill, L., Mawson, A., Humphris, J., Chou, A., Pajic, M., Scarlett, C., Pinho, A., Giry-Laterriere, M., Rooman, I., Samra, J., Kench, J., Lovell, J., Merrett, N., Toon, C., Epari, K., Nguyen, N., Barbour, A., Zeps, Nikolajs, Moran-Jones, K., Jamieson, N., Graham, J., Duthie, F., Oien, K., Hair, J., Gruetzmann, R., Maitra, A., Iacobuzio-Donahue, C., Wolfgang, C., Morgan, R., Lawlor, R., Corbo, V., Bassi, C., Rusev, B., Capelli, P., Salvia, R., Tortora, G., Mukhopadhyay, D., Petersen, G., Munzy, D., Fisher, W., Karim, S., Eshleman, J., Hruban, R., Pilarsky, C., Morton, J., Sansom, O., Scarpa, A., Musgrove, E., Bailey, U., Hofmann, O., Sutherland, R., Wheeler, D., Gill, A., Gibbs, R., Pearson, J., Biankin, A., and Grimmond, S.

Abstract

© 2016 Macmillan Publishers Limited. All rights reserved.Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63ΔN transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

Published
2016

41. OC-0529: A MR-based IGRT platform using the KPC transgenic mouse model of pancreatic cancer

Author

Thompson, J., primary, Beech, J., additional, Allen, D., additional, Gilchrist, S., additional, Newman, R., additional, Kinchesch, P., additional, Gomes, A., additional, D'Costa, Z., additional, Bird, L., additional, Vallis, K., additional, Boghozian, R., additional, Kavanagh, A., additional, Sansom, O., additional, Tullis, I., additional, Muschel, R., additional, Hill, M., additional, Vojnovic, B., additional, Smart, S., additional, and Fokas, E., additional

Published
2016
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43. Integrin signalling regulates YAP/TAZ to control skin homeostasis

Author

Elbediwy, A., primary, Vincent-Mistiaen, Z. I., additional, Spencer-Dene, B., additional, Stone, R. K., additional, Boeing, S., additional, Wculek, S. K., additional, Cordero, J., additional, Tan, E. H., additional, Ridgway, R., additional, Brunton, V. G., additional, Sahai, E., additional, Gerhardt, H., additional, Behrens, A., additional, Malanchi, I., additional, Sansom, O. J., additional, and Thompson, B. J., additional

Published
2016
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44. Frizzled7 functions as a Wnt receptor in intestinal epithelial Lgr5+ stem cells

Author

Flanagan, D., Phesse, T., Barker, N., Schwab, R., Amin, N., Malaterre, J., Stange, D., Nowell, C., Currie, S., Saw, J., Beuchert, E., Ramsay, R., Sansom, O., Ernst, M., Clevers, H., Vincan, Elizabeth, Flanagan, D., Phesse, T., Barker, N., Schwab, R., Amin, N., Malaterre, J., Stange, D., Nowell, C., Currie, S., Saw, J., Beuchert, E., Ramsay, R., Sansom, O., Ernst, M., Clevers, H., and Vincan, Elizabeth

Abstract

© 2015 The Authors. The mammalian adult small intestinal epithelium is a rapidly self-renewing tissue that is maintained by a pool of cycling stem cells intermingled with Paneth cells at the base of crypts. These crypt base stem cells exclusively express Lgr5 and require Wnt3 or, in its absence, Wnt2b. However, the Frizzled (Fzd) receptor that transmits these Wnt signals is unknown. We determined the expression profile of Fzd receptors in Lgr5+ stem cells, their immediate daughter cells, and Paneth cells. Here we show Fzd7 is enriched in Lgr5+ stem cells and binds Wnt3 and Wnt2b. Conditional deletion of the Fzd7 gene in adult intestinal epithelium leads to stem cell loss in vivo and organoid death in vitro. Crypts of conventional Fzd7 knockout mice show decreased basal Wnt signaling and impaired capacity to regenerate the epithelium following deleterious insult. These observations indicate that Fzd7 is required for robust Wnt-dependent processes in Lgr5+ intestinal stem cells.

Published
2015

46. P0282 : The long non coding RNA UC.158 modulates growth of Wnt/β;-catenin driven hepatocellular carcinoma (HCC)

Author

Cheong, I.H., primary, Lampis, A., additional, Fassan, M., additional, Paulus-Hock, V., additional, Vicentini, C., additional, Hahne, J., additional, Cascione, L., additional, Quagliata, L., additional, Jamieson, T., additional, Athineos, D., additional, Veronese, A., additional, Visone, R., additional, Murgia, C., additional, Ferrari, G., additional, Evans, T.R., additional, Feng, G.J., additional, Dale, T., additional, Boulter, L., additional, Guest, R., additional, Forbes, S., additional, Negrini, M., additional, Terracciano, L., additional, Scarpa, A., additional, Patel, T., additional, Workman, P., additional, Sansom, O., additional, Valeri, N., additional, and Braconi, C., additional

Published
2015
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47. 504 Frequent loss-of-function mutations in MLK4 suppresses signaling in the JNK-cJUN-p21/p15 pathway to promote growth of colon cancer cells

Author

Marusiak, A., primary, Stephenson, N., additional, Baik, H., additional, Trotter, E., additional, Li, Y., additional, Testoni, E., additional, Blyth, K., additional, Mason, S., additional, Puto, L., additional, Miller, C., additional, Hunter, T., additional, Sansom, O., additional, and Brognard, J., additional

Published
2014
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50. P64 THE ULTRACONSERVED NON CODING RNA UC.158 IS DOWNSTREAM OF THE WNT/b-CATENIN PATHWAY IN LIVER CANCERS

Author

Paulus-Hock, V., primary, Lampis, A., additional, Ferrari, G., additional, Boulton, L., additional, Guest, R., additional, Athineos, D., additional, Jamieson, T., additional, Veronese, A., additional, Visone, R., additional, Evans, R., additional, Feng, G.J., additional, Dale, T., additional, Negrini, M., additional, Forbes, S., additional, Patel, T., additional, Sansom, O., additional, Valeri, N., additional, and Braconi, C., additional

Published
2014
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