25 results on '"Perez-Mancera, Pedro A."'
Search Results
2. KrasP34R and KrasT58I mutations induce distinct RASopathy phenotypes in mice
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Wong, Jasmine C, Perez-Mancera, Pedro A, Huang, Tannie Q, Kim, Jangkyung, Grego-Bessa, Joaquim, del pilar Alzamora, Maria, Kogan, Scott C, Sharir, Amnon, Keefe, Susan H, Morales, Carolina E, Schanze, Denny, Castel, Pau, Hirose, Kentaro, Huang, Guo N, Zenker, Martin, Sheppard, Dean, Klein, Ophir, Tuveson, David, Braun, Benjamin S, and Shannon, Kevin
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Biomedical and Clinical Sciences ,Pediatric ,Lung ,Cancer ,Rare Diseases ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,Cardiomyopathies ,Craniosynostoses ,Female ,Hematologic Diseases ,Lung Diseases ,Male ,Mice ,Mice ,Inbred C57BL ,Mutation ,Pregnancy ,Proto-Oncogene Proteins p21(ras) ,Genetic diseases ,Mouse models ,Signal transduction ,Biomedical and clinical sciences ,Health sciences - Abstract
Somatic KRAS mutations are highly prevalent in many cancers. In addition, a distinct spectrum of germline KRAS mutations causes developmental disorders called RASopathies. The mutant proteins encoded by these germline KRAS mutations are less biochemically and functionally activated than those in cancer. We generated mice harboring conditional KrasLSL-P34Rand KrasLSL-T58I knock-in alleles and characterized the consequences of each mutation in vivo. Embryonic expression of KrasT58I resulted in craniofacial abnormalities reminiscent of those seen in RASopathy disorders, and these mice exhibited hyperplastic growth of multiple organs, modest alterations in cardiac valvulogenesis, myocardial hypertrophy, and myeloproliferation. By contrast, embryonic KrasP34R expression resulted in early perinatal lethality from respiratory failure due to defective lung sacculation, which was associated with aberrant ERK activity in lung epithelial cells. Somatic Mx1-Cre-mediated activation in the hematopoietic compartment showed that KrasP34R and KrasT58I expression had distinct signaling effects, despite causing a similar spectrum of hematologic diseases. These potentially novel strains are robust models for investigating the consequences of expressing endogenous levels of hyperactive K-Ras in different developing and adult tissues, for comparing how oncogenic and germline K-Ras proteins perturb signaling networks and cell fate decisions, and for performing preclinical therapeutic trials.
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- 2020
3. Designing a bio-inspired biomimetic in vitro system for the optimization of ex vivo studies of pancreatic cancer
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Totti, Stella, Vernardis, Spyros I., Meira, Lisiane, Pérez-Mancera, Pedro A., Costello, Eithne, Greenhalf, William, Palmer, Daniel, Neoptolemos, John, Mantalaris, Athanasios, and Velliou, Eirini G.
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- 2017
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4. BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model
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Perna, Daniele, Karreth, Florian A., Rust, Alistair G., Perez-Mancera, Pedro A., Rashid, Mamunur, Iorio, Francesco, Alifrangis, Constantine, Arends, Mark J., Bosenberg, Marcus W., Bollag, Gideon, Tuveson, David A., and Adams, David J.
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- 2015
5. What We Have Learned About Pancreatic Cancer From Mouse Models
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Pérez–Mancera, Pedro A., Guerra, Carmen, Barbacid, Mariano, and Tuveson, David A.
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- 2012
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6. The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma
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Perez-Mancera, Pedro A., Rust, Alistair G., van der Weyden, Louise, Kristiansen, Glen, Li, Allen, Sarver, Aaron L., Silverstein, Kevin A.T., Grutzmann, Robert, Aust, Daniela, Rummele, Petra, Knosel, Thomas, Herd, Colin, Stemple, Derek L., Kettleborough, Ross, Brosnan, Jacqueline A., Li, Ang, Morgan, Richard, Knight, Spencer, Yu, Jun, Stegeman, Shane, Collier, Lara S., ten Hoeve, Jelle J., de Ridder, Jeroen, Klein, Alison P., Goggins, Michael, Hruban, Ralph H., Chang, David K., Biankin, Andrew V., Grimmond, Sean M., Wessels, Lodewyk F.A., Wood, Stephen A., Iacobuzio-Donahue, Christine A., Pilarsky, Christian, Largaespada, David A., Adams, David J., and Tuveson, David A.
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Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations (1-4) in addition to numerous lower frequency genetic events of uncertain significance (5). Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis (6,7) in a mouse model of pancreatic ductal preneoplasia (8) to identify genes that cooperate with oncogenic [Kras.sup.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 (9), 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.sup.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., The biological sequelae of PDA has been partially attributed to frequent and well characterized mutations in KRAS (>90%), CDKN2A (>90%), TP53 (70%) and SMAD4 (55%) (1-4). Recent genomewide analyses have [...]
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- 2012
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7. STAG2 is a clinically relevant tumor suppressor in pancreatic ductal adenocarcinoma
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Evers, Lisa, Perez-Mancera, Pedro A, Lenkiewicz, Elizabeth, Tang, Nanyun, Aust, Daniela, Knösel, Thomas, Rümmele, Petra, Holley, Tara, Kassner, Michelle, Aziz, Meraj, Ramanathan, Ramesh K, Von Hoff, Daniel D, Yin, Holly, Pilarsky, Christian, and Barrett, Michael T
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- 2014
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8. Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry
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Sage, Julien, Miller, Abigail L., Perez-Mancera, Pedro A., Wysocki, Julianne M., and Jacks, Tyler
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Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Author(s): Julien Sage [1]; Abigail L. Miller [1]; Pedro A. Pérez-Mancera [3]; Julianne M. Wysocki [1]; Tyler Jacks (corresponding author) [1, 2] Cancer cells arise from normal cells through the [...]
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- 2003
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9. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes
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Biankin, Andrew V., Waddell, Nicola, Kassahn, Karin S., Gingras, Marie-Claude, Muthuswamy, Lakshmi B., Johns, Amber L., Miller, David K., Wilson, Peter J., Patch, Ann-Marie, Wu, Jianmin, Chang, David K., Cowley, Mark J., Gardiner, Brooke B., Song, Sarah, Harliwong, Ivon, Idrisoglu, Senel, Nourse, Craig, Nourbakhsh, Ehsan, Manning, Suzanne, Wani, Shivangi, Gongora, Milena, Pajic, Marina, Scarlett, Christopher J., Gill, Anthony J., Pinho, Andreia V., Rooman, Ilse, Anderson, Matthew, Holmes, Oliver, Leonard, Conrad, Taylor, Darrin, Wood, Scott, Xu, Qinying, Nones, Katia, Lynn Fink, J., Christ, Angelika, Bruxner, Tim, Cloonan, Nicole, Kolle, Gabriel, Newell, Felicity, Pinese, Mark, Scott Mead, R., Humphris, Jeremy L., Kaplan, Warren, Jones, Marc D., Colvin, Emily K., Nagrial, Adnan M., Humphrey, Emily S., Chou, Angela, Chin, Venessa T., Chantrill, Lorraine A., Mawson, Amanda, Samra, Jaswinder S., Kench, James G., Lovell, Jessica A., Daly, Roger J., Merrett, Neil D., Toon, Christopher, Epari, Krishna, Nguyen, Nam Q., Barbour, Andrew, Zeps, Nikolajs, Brancato, Mary-Anne L., Rowe, Sarah J., Simpson, Skye L., Martyn-Smith, Mona, Thomas, Michelle T., Pettit, Jessica, Tao, Jiang, DiPietro, Renee, Watson, Clare, Wong, Rachel, Giry-Laterriere, Marc, Pavlakis, Nick, Guminski, Alex, Asghari, Ray, Pavey, Darren A., Das, Amitabha, Cosman, Peter H., Ismail, Kasim, O’Connor, Chelsie, Lam, Vincent W., McLeod, Duncan, Pleass, Henry C., Richardson, Arthur, James, Virginia, Cooper, Caroline L., Joseph, David, Sandroussi, Charbel, Crawford, Michael, Gallagher, James, Texler, Michael, Forrest, Cindy, Laycock, Andrew, Epari, Krishna P., Ballal, Mo, Fletcher, David R., Mukhedkar, Sanjay, Spry, Nigel A., DeBoer, Bastiaan, Chai, Ming, Beilin, Maria, Feeney, Kynan, Ruszkiewicz, Andrew R., Worthley, Chris, Tan, Chuan P., Debrencini, Tamara, Chen, John, Brooke-Smith, Mark E., Papangelis, Virginia, Tang, Henry, Barbour, Andrew P., Clouston, Andrew D., Martin, Patrick, O’Rourke, Thomas J., Chiang, Amy, Fawcett, Jonathan W., Slater, Kellee, Yeung, Shinn, Hatzifotis, Michael, Hodgkinson, Peter, Christophi, Christopher, Nikfarjam, Mehrdad, Mountain Victorian Cancer Biobank, Angela, Eshleman, James R., Schulick, Richard D., Wolfgang, Christopher L., Morgan, Richard A., Hodgin, Mary B., Lawlor, Rita T., Capelli, Paola, Beghelli, Stefania, Corbo, Vincenzo, Scardoni, Maria, Pederzoli, Paolo, Tortora, Giampaolo, Bassi, Claudio, Kakkar, Nipun, Zhao, Fengmei, Qing Wu, Yuan, Wang, Min, Muzny, Donna M., Fisher, William E., Charles Brunicardi, F., Hodges, Sally E., Reid, Jeffrey G., Drummond, Jennifer, Chang, Kyle, Han, Yi, Lewis, Lora R., Dinh, Huyen, Buhay, Christian J., Beck, Timothy, Timms, Lee, Sam, Michelle, Begley, Kimberly, Brown, Andrew, Pai, Deepa, Panchal, Ami, Buchner, Nicholas, De Borja, Richard, Denroche, Robert E., Yung, Christina K., Serra, Stefano, Onetto, Nicole, Mukhopadhyay, Debabrata, Tsao, Ming-Sound, Shaw, Patricia A., Petersen, Gloria M., Gallinger, Steven, Hruban, Ralph H., Maitra, Anirban, Iacobuzio-Donahue, Christine A., Tempero, Margaret A., Mann, Karen M., Jenkins, Nancy A., Perez-Mancera, Pedro A., Adams, David J., Largaespada, David A., Wessels, Lodewyk F. A., Rust, Alistair G., Stein, Lincoln D., Tuveson, David A., Copeland, Neal G., Musgrove, Elizabeth A., Scarpa, Aldo, Hudson, Thomas J., Sutherland, Robert L., Wheeler, David A., Pearson, John V., McPherson, John D., Gibbs, Richard A., and Grimmond, Sean M.
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- 2012
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10. SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia
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Pearson, Helen B., Perez-Mancera, Pedro A., Dow, Lukas E., Ryan, Andrew, Tennstedt, Pierre, Bogani, Debora, Elsum, Imogen, Greenfield, Andy, Tuveson, David A., Simon, Ronald, and Humbert, Patrick O.
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- 2011
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11. ZNF703 is a common Luminal B breast cancer oncogene that differentially regulates luminal and basal progenitors in human mammary epithelium
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Holland, Daniel G., Burleigh, Angela, Git, Anna, Goldgraben, Mae A., Perez-Mancera, Pedro A., Chin, Suet-Feung, Hurtado, Antonio, Bruna, Alejandra, Ali, Raza H., Greenwood, Wendy, Dunning, Mark J., Samarajiwa, Shamith, Menon, Suraj, Rueda, Oscar M., Lynch, Andy G., McKinney, Steven, Ellis, Ian O., Eaves, Connie J., Carroll, Jason S., Curtis, Christina, Aparicio, Samuel, and Caldas, Carlos
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- 2011
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12. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma
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Varela, Ignacio, Tarpey, Patrick, Raine, Keiran, Huang, Dachuan, Ong, Choon Kiat, Stephens, Philip, Davies, Helen, Jones, David, Lin, Meng-Lay, Teague, Jon, Bignell, Graham, Butler, Adam, Cho, Juok, Dalgliesh, Gillian L., Galappaththige, Danushka, Greenman, Chris, Hardy, Claire, Jia, Mingming, Latimer, Calli, Lau, King Wai, Marshall, John, McLaren, Stuart, Menzies, Andrew, Mudie, Laura, Stebbings, Lucy, Largaespada, David A., Wessels, L. F. A., Richard, Stephane, Kahnoski, Richard J., Anema, John, Tuveson, David A., Perez-Mancera, Pedro A., Mustonen, Ville, Fischer, Andrej, Adams, David J., Rust, Alistair, Chan-on, Waraporn, Subimerb, Chutima, Dykema, Karl, Furge, Kyle, Campbell, Peter J., Teh, Bin Tean, Stratton, Michael R., and Futreal, Andrew P.
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- 2011
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13. ON THE DEVELOPMENT OF A BIOINSPIRED, BIOMIMETIC PANCREATIC CANCER MODEL: ENGINEERING A HYBRID SCAFFOLD ASSISTED IN VITRO MULTICELLULAR MODEL OF PANCREATIC CANCER
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Gupta, Priyanka, Pérez-Mancera, Pedro A., Kocher, Hemant, Nisbet, Andrew, Schettino, Giuseppe, and Velliou, Eirini G.
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- 2020
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14. PDAC-associated fibroblasts are less responsive to an anti-fibrotic stimulus and more responsive to a positive regulator of fibroblast activation than normal activated fibroblasts
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Barrera, Lawrence N., Evans, Anthony, Lane, Brian, Brumskill, Sarah, Oldfield, Frances, Campbell, Fioana, Andrews, Timothy, Lu, Zipeng, Perez-Mancera, Pedro A., Liloglou, Triantafillos, Jalali, Mehdi, Dawson, Rebecca, Nunes, Quentin, Phillips, Phoebe, Timms, John F., Menon, Usha, Halloran, Christopher, Greenhalf, William, Neoptolemos, John P., and Costello, Eithne
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- 2019
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15. The efficacy of brusatol as a chemotherapeutic agent in pancreatic cancer and its relevance to potential chemoresistance conferred by Nrf2
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Williams, Dylan, Gayon, Susana, Barrera, Lawrence, Perez-Mancera, Pedro, Copple, Ian, Goldring, Christopher, Greenhalf, William, and Costello, Eithne
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- 2018
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16. Disease associated fibroblasts from various pancreatic disorders exhibit subtype specific genetic profile
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Barrera, Lawrence, Evans, Anthony, Lane, Brian, Brumskill, Sarah, Oldfield, Frances, Campbell, Fioana, Andrews, Timothy, Perez-Mancera, Pedro, Liloglou, Triantafillos, Phillips, Phoebe, Halloran, Christopher, Greenhalf, William, Neoptolemos, John P., and Costello, Eithne
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- 2018
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17. Identification of novel signalling pathways dysregulated in pancreatic cancer-associated fibroblasts
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Barrera, Lawrence, Lane, Brian, Brumskill, Sarah, Oldfield, Frances, Lamond, Rebecca, Wilkinson, Luke, Bermejo-Rodriguez, Camino, Aughton, Karen, Sanna, Roberta, Nunes, Quentin, Perez-Mancera, Pedro, Campbell, Fiona, Andrews, Timothy, Phillips, Phoebe, Halloran, Christopher, Sutton, Robert, Greenhalf, William, Neoptolemos, John, and Costello, Eithne
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- 2016
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18. The radioresistance biological function of the SCF/kit signaling pathway is mediated by the zinc-finger transcription factor Slug.
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Perez-Losada, Jesus, Sanchez-Martin, Manuel, Perez-Caro, Maria, Perez-Mancera, Pedro A, and Sanchez-Garcia, Isidro
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ZINC-finger proteins ,TRANSCRIPTION factors ,HEMATOPOIESIS ,STEM cells ,CELLULAR signal transduction - Abstract
Radiation-induced destruction of the hematopoietic system is the primary cause of death based on the findings that transfer of normal bone marrow cells prevents death from lethal irradiation. The stem cell factor-c-kit signaling pathway (SCF/c-kit) has been previously implicated in the hematopoietic recovery which prevents death from lethal irradiation, but the molecular mechanisms that mediate this biological effect are unknown. Since mutations on SCF, c-kit and Slug genes have a similar phenotype in mice, we examined if Slug could complement the radiosensitivity of kit-deficient mice. In this report, we show that Slug acts as a radioprotection agent as lack of Slug results in increased radiosensitivity. This effect cannot be recovered by activating SCF/c-kit in lethally irradiated Slug-deficient mice, as SCF-treated mice did not demonstrate stimulation of hematopoietic recovery leading to survival of the Slug-deficient mice. We found that we could complement the hematopoietic failure in lethally irradiated c-kit-deficient mice by transducing them with a TAT-Slug protein. We conclude that the zinc-finger transcription factor Slug is absolutely necessary for survival from lethal irradiation and identify Slug as the molecular target that mediates the radioprotection through SCF/c-kit. These results indicate that Slug may be a molecular component conferring radioresistance to cancer cells.Oncogene (2003) 22, 4205-4211. doi:10.1038/sj.onc.1206467 [ABSTRACT FROM AUTHOR]
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- 2003
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19. Expression of the FUS domain restores liposarcoma development in CHOP transgenic mice.
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Perez-Mancera, Pedro Antonio, Perez-Losada, Jesus, Sanchez-Martin, Manuel, Rodriguez-Garcia, Maria Aranzazu, Flores, Teresa, Battaner, Enrique, Guttierez-Adan, Alfonso, Pintado, Belen, and Sanchez-Garcia, Isidro
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PROTEINS , *LIPOSARCOMA , *MESENCHYME tumors - Abstract
Presents a study that examined the role of the expression of FUS domain in the restoration of liposarcoma development in CHOP-transgenic mice. Components of mesenchymal cancer development; Characteristics of liposarcoma; Information on the FUS-CHOP fusion; Functions of the FUS component of the fusion protein.
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- 2002
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20. In Vivo Identification of Tumor- Suppressive PTEN ceRNAs in an Oncogenic BRAF-Induced Mouse Model of Melanoma
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Karreth, Florian A., Tay, Yvonne, Perna, Daniele, Ala, Ugo, Tan, Shen Mynn, Rust, Alistair G., DeNicola, Gina, Webster, Kaitlyn A., Weiss, Dror, Perez-Mancera, Pedro A., Krauthammer, Michael, Halaban, Ruth, Provero, Paolo, Adams, David J., Tuveson, David A., and Pandolfi, Pier Paolo
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TUMOR suppressor proteins , *ONCOGENES , *MELANOMA , *NON-coding RNA , *GENETIC regulation , *GENETIC transcription , *MUTAGENESIS , *LABORATORY mice - Abstract
Summary: We recently proposed that competitive endogenous RNAs (ceRNAs) sequester microRNAs to regulate mRNA transcripts containing common microRNA recognition elements (MREs). However, the functional role of ceRNAs in cancer remains unknown. Loss of PTEN, a tumor suppressor regulated by ceRNA activity, frequently occurs in melanoma. Here, we report the discovery of significant enrichment of putative PTEN ceRNAs among genes whose loss accelerates tumorigenesis following Sleeping Beauty insertional mutagenesis in a mouse model of melanoma. We validated several putative PTEN ceRNAs and further characterized one, the ZEB2 transcript. We show that ZEB2 modulates PTEN protein levels in a microRNA-dependent, protein coding-independent manner. Attenuation of ZEB2 expression activates the PI3K/AKT pathway, enhances cell transformation, and commonly occurs in human melanomas and other cancers expressing low PTEN levels. Our study genetically identifies multiple putative microRNA decoys for PTEN, validates ZEB2 mRNA as a bona fide PTEN ceRNA, and demonstrates that abrogated ZEB2 expression cooperates with BRAFV600E to promote melanomagenesis. [ABSTRACT FROM AUTHOR]
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- 2011
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21. Scribble Deficiency Promotes Pancreatic Ductal Adenocarcinoma Development and Metastasis.
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Bermejo-Rodriguez C, Araos Henríquez J, Caligiuri G, Pinto Teles S, Park Y, Evans A, Barrera LN, Neesse A, Grutzmann R, Aust D, Rümmele P, Knösel T, Narita M, Narita M, Campbell F, Öhlund D, Pilarsky C, Dow LE, Humbert PO, Biffi G, Tuveson DA, and Perez-Mancera PA
- Abstract
Perturbation of cell polarity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) progression. Scribble (SCRIB) is a well characterized polarity regulator that has diverse roles in the pathogenesis of human neoplasms. To investigate the impact of SCRIB deficiency on PDAC development and progression, Scrib was genetically ablated in well-established mouse models of PDAC. Scrib loss in combination with KrasG12D did not influence development of pancreatic intraepithelial neoplasms (PanIN) in mice. However, Scrib deletion cooperated with KrasG12D and concomitant Trp53 heterozygous deletion to promote invasive PDAC and metastatic dissemination, leading to reduced overall survival. Immunohistochemical and transcriptome analyses revealed that Scrib-null tumors display a pronounced reduction of collagen content and cancer associated fibroblast (CAF) abundance. Mechanistically, interleukin 1α (IL1α) levels were reduced in Scrib deficient tumors, and Scrib knockdown downregulated IL1α in mouse PDAC organoids (mPDOs), which impaired CAF activation. Furthermore, Scrib loss increased YAP activation in mPDOs and established PDAC cell lines, enhancing cell survival. Clinically, SCRIB expression was decreased in human PDAC, and SCRIB mislocalization was associated with poorer patient outcome. These results indicate that SCRIB deficiency enhances cancer cell survival and remodels the tumor microenvironment to accelerate PDAC development and progression, establishing the tumor suppressor function of SCRIB in advanced pancreatic cancer.
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- 2024
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22. Fibroblasts from Distinct Pancreatic Pathologies Exhibit Disease-Specific Properties.
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Barrera LN, Evans A, Lane B, Brumskill S, Oldfield FE, Campbell F, Andrews T, Lu Z, Perez-Mancera PA, Liloglou T, Ashworth M, Jalali M, Dawson R, Nunes Q, Phillips PA, Timms JF, Halloran C, Greenhalf W, Neoptolemos JP, and Costello E
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- Adenocarcinoma genetics, Adenocarcinoma metabolism, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal metabolism, Cell Movement, Cell Proliferation, Fibroblasts metabolism, Humans, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism, Tenascin genetics, Tenascin metabolism, Transforming Growth Factor beta1 genetics, Transforming Growth Factor beta1 metabolism, Tumor Cells, Cultured, Adenocarcinoma pathology, Carcinoma, Pancreatic Ductal pathology, Fibroblasts pathology, Gene Expression Regulation, Neoplastic, MicroRNAs genetics, Pancreatic Neoplasms pathology
- Abstract
Although fibrotic stroma forms an integral component of pancreatic diseases, whether fibroblasts programmed by different types of pancreatic diseases are phenotypically distinct remains unknown. Here, we show that fibroblasts isolated from patients with pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis (CP), periampullary tumors, and adjacent normal (NA) tissue ( N = 34) have distinct mRNA and miRNA profiles. Compared with NA fibroblasts, PDAC-associated fibroblasts were generally less sensitive to an antifibrotic stimulus (NPPB) and more responsive to positive regulators of activation such as TGFβ1 and WNT. Of the disease-associated fibroblasts examined, PDAC- and CP-derived fibroblasts shared greatest similarity, yet PDAC-associated fibroblasts expressed higher levels of tenascin C (TNC), a finding attributable to miR-137, a novel regulator of TNC. TNC protein and transcript levels were higher in PDAC tissue versus CP tissue and were associated with greater levels of stromal activation, and conditioned media from TNC-depleted PDAC-associated fibroblasts modestly increased both PDAC cell proliferation and PDAC cell migration, indicating that stromal TNC may have inhibitory effects on PDAC cells. Finally, circulating TNC levels were higher in patients with PDAC compared with CP. Our characterization of pancreatic fibroblast programming as disease-specific has consequences for therapeutic targeting and for the manner in which fibroblasts are used in research. SIGNIFICANCE: Primary fibroblasts derived from various types of pancreatic diseases possess and retain distinct molecular and functional characteristics in culture, providing a series of cellular models for treatment development and disease-specific research., (©2020 American Association for Cancer Research.)
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- 2020
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23. Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer.
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Humpton TJ, Alagesan B, DeNicola GM, Lu D, Yordanov GN, Leonhardt CS, Yao MA, Alagesan P, Zaatari MN, Park Y, Skepper JN, Macleod KF, Perez-Mancera PA, Murphy MP, Evan GI, Vousden KH, and Tuveson DA
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- Animals, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal metabolism, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Glycolysis, Humans, Membrane Proteins genetics, Mice, Mitophagy, Mutation, NADP metabolism, Neoplasm Transplantation, Oxidation-Reduction, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins p21(ras) metabolism, Tumor Suppressor Proteins genetics, Carcinoma, Pancreatic Ductal pathology, Membrane Proteins metabolism, Mitochondria metabolism, Pancreatic Neoplasms pathology, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins p21(ras) genetics, Tumor Suppressor Proteins metabolism
- Abstract
Activating KRAS mutations are found in nearly all cases of pancreatic ductal adenocarcinoma (PDAC), yet effective clinical targeting of oncogenic KRAS remains elusive. Understanding of KRAS-dependent PDAC-promoting pathways could lead to the identification of vulnerabilities and the development of new treatments. We show that oncogenic KRAS induces BNIP3L /NIX expression and a selective mitophagy program that restricts glucose flux to the mitochondria and enhances redox capacity. Loss of Nix restores functional mitochondria to cells, increasing demands for NADPH reducing power and decreasing proliferation in glucose-limited conditions. Nix deletion markedly delays progression of pancreatic cancer and improves survival in a murine (KPC) model of PDAC. Although conditional Nix ablation in vivo initially results in the accumulation of mitochondria, mitochondrial content eventually normalizes via increased mitochondrial clearance programs, and pancreatic intraepithelial neoplasia (PanIN) lesions progress to PDAC. We identify the KRAS-NIX mitophagy program as a novel driver of glycolysis, redox robustness, and disease progression in PDAC. SIGNIFICANCE: NIX-mediated mitophagy is a new oncogenic KRAS effector pathway that suppresses functional mitochondrial content to stimulate cell proliferation and augment redox homeostasis. This pathway promotes the progression of PanIN to PDAC and represents a new dependency in pancreatic cancer. This article is highlighted in the In This Issue feature, p. 1143 ., (©2019 American Association for Cancer Research.)
- Published
- 2019
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24. Tissue-Specific Oncogenic Activity of KRAS A146T .
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Poulin EJ, Bera AK, Lu J, Lin YJ, Strasser SD, Paulo JA, Huang TQ, Morales C, Yan W, Cook J, Nowak JA, Brubaker DK, Joughin BA, Johnson CW, DeStefanis RA, Ghazi PC, Gondi S, Wales TE, Iacob RE, Bogdanova L, Gierut JJ, Li Y, Engen JR, Perez-Mancera PA, Braun BS, Gygi SP, Lauffenburger DA, Westover KD, and Haigis KM
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- Cell Transformation, Neoplastic genetics, Humans, Models, Molecular, Neoplasms genetics, Neoplasms metabolism, Neoplasms pathology, Organ Specificity, Phenotype, Protein Conformation, Proteome, Proteomics methods, Proto-Oncogene Proteins p21(ras) chemistry, Proto-Oncogene Proteins p21(ras) metabolism, Structure-Activity Relationship, Alleles, Mutation, Oncogenes, Proto-Oncogene Proteins p21(ras) genetics
- Abstract
KRAS is the most frequently mutated oncogene. The incidence of specific KRAS alleles varies between cancers from different sites, but it is unclear whether allelic selection results from biological selection for specific mutant KRAS proteins. We used a cross-disciplinary approach to compare KRAS
G12D , a common mutant form, and KRASA146T , a mutant that occurs only in selected cancers. Biochemical and structural studies demonstrated that KRASA146T exhibits a marked extension of switch 1 away from the protein body and nucleotide binding site, which activates KRAS by promoting a high rate of intrinsic and guanine nucleotide exchange factor-induced nucleotide exchange. Using mice genetically engineered to express either allele, we found that KRASG12D and KRASA146T exhibit distinct tissue-specific effects on homeostasis that mirror mutational frequencies in human cancers. These tissue-specific phenotypes result from allele-specific signaling properties, demonstrating that context-dependent variations in signaling downstream of different KRAS mutants drive the KRAS mutational pattern seen in cancer. SIGNIFICANCE: Although epidemiologic and clinical studies have suggested allele-specific behaviors for KRAS , experimental evidence for allele-specific biological properties is limited. We combined structural biology, mass spectrometry, and mouse modeling to demonstrate that the selection for specific KRAS mutants in human cancers from different tissues is due to their distinct signaling properties. See related commentary by Hobbs and Der, p. 696 . This article is highlighted in the In This Issue feature, p. 681 ., (©2019 American Association for Cancer Research.)- Published
- 2019
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25. Chemoresistance in Pancreatic Cancer Is Driven by Stroma-Derived Insulin-Like Growth Factors.
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Ireland L, Santos A, Ahmed MS, Rainer C, Nielsen SR, Quaranta V, Weyer-Czernilofsky U, Engle DD, Perez-Mancera PA, Coupland SE, Taktak A, Bogenrieder T, Tuveson DA, Campbell F, Schmid MC, and Mielgo A
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- Animals, Cell Line, Tumor, Cell Proliferation, Humans, Mice, Pancreatic Neoplasms pathology, Signal Transduction, Pancreatic Neoplasms genetics, Somatomedins genetics
- Abstract
Tumor-associated macrophages (TAM) and myofibroblasts are key drivers in cancer that are associated with drug resistance in many cancers, including pancreatic ductal adenocarcinoma (PDAC). However, our understanding of the molecular mechanisms by which TAM and fibroblasts contribute to chemoresistance is unclear. In this study, we found that TAM and myofibroblasts directly support chemoresistance of pancreatic cancer cells by secreting insulin-like growth factors (IGF) 1 and 2, which activate insulin/IGF receptors on pancreatic cancer cells. Immunohistochemical analysis of biopsies from patients with pancreatic cancer revealed that 72% of the patients expressed activated insulin/IGF receptors on tumor cells, and this positively correlates with increased CD163
+ TAM infiltration. In vivo, we found that TAM and myofibroblasts were the main sources of IGF production, and pharmacologic blockade of IGF sensitized pancreatic tumors to gemcitabine. These findings suggest that inhibition of IGF in combination with chemotherapy could benefit patients with PDAC, and that insulin/IGF1R activation may be used as a biomarker to identify patients for such therapeutic intervention. Cancer Res; 76(23); 6851-63. ©2016 AACR., (©2016 American Association for Cancer Research.)- Published
- 2016
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