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1. 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

2. 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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3. 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

4. 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

5. 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

6. 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

7. 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

8. GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine

Author

Ferro, R., Adamska, A., Lattanzio, R., Mavrommati, I., Edling, C., Arifin, S., Fyffe, C., Sala, G., Sacchetto, L., Chiorino, G., De Laurenzi, V., Piantelli, M., Sansom, O., Maffucci, T., Falasca, Marco, Ferro, R., Adamska, A., Lattanzio, R., Mavrommati, I., Edling, C., Arifin, S., Fyffe, C., Sala, G., Sacchetto, L., Chiorino, G., De Laurenzi, V., Piantelli, M., Sansom, O., Maffucci, T., and Falasca, Marco

Abstract

© 2018, Macmillan Publishers Limited, part of Springer Nature. The life expectancy for pancreatic cancer patients has seen no substantial changes in the last 40 years as very few and mostly just palliative treatments are available. As the five years survival rate remains around 5%, the identification of novel pharmacological targets and development of new therapeutic strategies are urgently needed. Here we demonstrate that inhibition of the G protein-coupled receptor GPR55, using genetic and pharmacological approaches, reduces pancreatic cancer cell growth in vitro and in vivo and we propose that this may represent a novel strategy to inhibit pancreatic ductal adenocarcinoma (PDAC) progression. Specifically, we show that genetic ablation of Gpr55 in the KRASWT/G12D/TP53WT/R172H/Pdx1-Cre+/+ (KPC) mouse model of PDAC significantly prolonged survival. Importantly, KPC mice treated with a combination of the GPR55 antagonist Cannabidiol (CBD) and gemcitabine (GEM, one of the most used drugs to treat PDAC), survived nearly three times longer compared to mice treated with vehicle or GEM alone. Mechanistically, knockdown or pharmacologic inhibition of GPR55 reduced anchorage-dependent and independent growth, cell cycle progression, activation of mitogen-activated protein kinase (MAPK) signalling and protein levels of ribonucleotide reductases in PDAC cells. Consistent with this, genetic ablation of Gpr55 reduced proliferation of tumour cells, MAPK signalling and ribonucleotide reductase M1 levels in KPC mice. Combination of CBD and GEM inhibited tumour cell proliferation in KPC mice and it opposed mechanisms involved in development of resistance to GEM in vitro and in vivo. Finally, we demonstrate that the tumour suppressor p53 regulates GPR55 protein expression through modulation of the microRNA miR34b-3p. Our results demonstrate the important role played by GPR55 downstream of p53 in PDAC progression. Moreover our data indicate that combination of CBD and GEM, both curren

Published
2018

9. 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

10. 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

11. Genomic analyses identify molecular subtypes of pancreatic cancer

Author

Bailey, P., Chang, D. K., Nones, K., Johns, A. L., Patch, A. -M., Gingras, M. -C., Miller, D. K., Christ, A. N., Bruxner, T. J. C., Quinn, M. C., Nourse, C., Murtaugh, L. C., Harliwong, I., Idrisoglu, S., Manning, S., Nourbakhsh, E., Wani, S., Fink, L., Holmes, O., Chin, V., Anderson, M. J., Kazakoff, S., Leonard, C., Newell, F., Waddell, N., Wood, S., Xu, Q., Wilson, P. J., Cloonan, N., Kassahn, K. S., Taylor, D., Quek, K., Robertson, A., Pantano, L., Mincarelli, L., Sanchez, L. N., Evers, L., Wu, J., Pinese, M., Cowley, M. J., Jones, M. D., Colvin, E. K., Nagrial, A. M., Humphrey, E. S., Chantrill, L. A., Mawson, A., Humphris, J., Chou, A., Pajic, M., Scarlett, C. J., Pinho, A. V., Giry-Laterriere, M., Rooman, I., Samra, J. S., Kench, J. G., Lovell, J. A., Merrett, N. D., Toon, C. W., Epari, K., Nguyen, N. Q., Barbour, A., Zeps, N., Moran-Jones, K., Jamieson, N. B., Graham, J. S., Duthie, F., Oien, K., Hair, J., Grutzmann, R., Maitra, A., Iacobuzio-Donahue, C. A., Wolfgang, C. L., Morgan, R. A., Lawlor, R. T., Corbo, V., Bassi, C., Rusev, B., Capelli, P., Salvia, R., Tortora, G., Mukhopadhyay, D., Petersen, G. M., Munzy, D. M., Fisher, W. E., Karim, S. A., Eshleman, J. R., Hruban, R. H., Pilarsky, C., Morton, J. P., Sansom, O. J., Scarpa, A., Musgrove, E. A., Bailey, U. -M. H., Hofmann, O., Sutherland, R. L., Wheeler, D. A., Gill, A. J., Gibbs, R. A., Pearson, J. V., Biankin, A. V., Grimmond, S. M., Tortora G. (ORCID:0000-0002-1378-4962), Bailey, P., Chang, D. K., Nones, K., Johns, A. L., Patch, A. -M., Gingras, M. -C., Miller, D. K., Christ, A. N., Bruxner, T. J. C., Quinn, M. C., Nourse, C., Murtaugh, L. C., Harliwong, I., Idrisoglu, S., Manning, S., Nourbakhsh, E., Wani, S., Fink, L., Holmes, O., Chin, V., Anderson, M. J., Kazakoff, S., Leonard, C., Newell, F., Waddell, N., Wood, S., Xu, Q., Wilson, P. J., Cloonan, N., Kassahn, K. S., Taylor, D., Quek, K., Robertson, A., Pantano, L., Mincarelli, L., Sanchez, L. N., Evers, L., Wu, J., Pinese, M., Cowley, M. J., Jones, M. D., Colvin, E. K., Nagrial, A. M., Humphrey, E. S., Chantrill, L. A., Mawson, A., Humphris, J., Chou, A., Pajic, M., Scarlett, C. J., Pinho, A. V., Giry-Laterriere, M., Rooman, I., Samra, J. S., Kench, J. G., Lovell, J. A., Merrett, N. D., Toon, C. W., Epari, K., Nguyen, N. Q., Barbour, A., Zeps, N., Moran-Jones, K., Jamieson, N. B., Graham, J. S., Duthie, F., Oien, K., Hair, J., Grutzmann, R., Maitra, A., Iacobuzio-Donahue, C. A., Wolfgang, C. L., Morgan, R. A., Lawlor, R. T., Corbo, V., Bassi, C., Rusev, B., Capelli, P., Salvia, R., Tortora, G., Mukhopadhyay, D., Petersen, G. M., Munzy, D. M., Fisher, W. E., Karim, S. A., Eshleman, J. R., Hruban, R. H., Pilarsky, C., Morton, J. P., Sansom, O. J., Scarpa, A., Musgrove, E. A., Bailey, U. -M. H., Hofmann, O., Sutherland, R. L., Wheeler, D. A., Gill, A. J., Gibbs, R. A., Pearson, J. V., Biankin, A. V., Grimmond, S. M., and Tortora G. (ORCID:0000-0002-1378-4962)

Published
2016

12. Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells

Author

Spender, L C, Ferguson, G J, Liu, S, Cui, C, Girotti, M R, Sibbet, G, Higgs, E B, Shuttleworth, M K, Hamilton, T, Lorigan, P, Weller, M, Vincent, D F, Sansom, O J, Frame, M, ten Dijke, P, Marais, Richard, Inman, G J, Spender, L C, Ferguson, G J, Liu, S, Cui, C, Girotti, M R, Sibbet, G, Higgs, E B, Shuttleworth, M K, Hamilton, T, Lorigan, P, Weller, M, Vincent, D F, Sansom, O J, Frame, M, ten Dijke, P, Marais, Richard, and Inman, G J

Published
2016

13. 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

14. 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

15. Paneth Cells in Intestinal Homeostasis and Tissue Injury

Author

Roth, S, Franken, Patrick, Sacchetti, Andrea, Kremer, Andreas, Anderson, K, Sansom, O, Fodde, Riccardo, Roth, S, Franken, Patrick, Sacchetti, Andrea, Kremer, Andreas, Anderson, K, Sansom, O, and Fodde, Riccardo

Abstract

Adult stem cell niches are often co-inhabited by cycling and quiescent stem cells. In the intestine, lineage tracing has identified Lgr5(+) cells as frequently cycling stem cells, whereas Bmi1(+), mTert(+), Hopx(+) and Lrig1(+) cells appear to be more quiescent. Here, we have applied a non-mutagenic and cell cycle independent approach to isolate and characterize small intestinal label-retaining cells (LRCs) persisting in the lower third of the crypt of Lieberkuhn for up to 100 days. LRCs do not express markers of proliferation and of enterocyte, goblet or enteroendocrine differentiation, but are positive for Paneth cell markers. While during homeostasis, LR/Paneth cells appear to play a supportive role for Lgr5(+) stem cells as previously shown, upon tissue injury they switch to a proliferating state and in the process activate Bmi1 expression while silencing Paneth-specific genes. Hence, they are likely to contribute to the regenerative process following tissue insults such as chronic inflammation.

Published
2012

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