Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice
Sunil R. Hingorani,Lifu Wang,Asha S. Multani,Chelsea Combs,Therese B. Deramaudt,Ralph H. Hruban,Anil K. Rustgi,Sandy Chang,David A. Tuveson +8 more
TLDR
Targeted concomitant endogenous expression of Trp53(R172H) and Kras(G12D) to the mouse pancreas reveals the cooperative development of invasive and widely metastatic carcinoma that recapitulates the human disease.About:
This article is published in Cancer Cell.The article was published on 2005-05-01 and is currently open access. It has received 2082 citations till now. The article focuses on the topics: KRAS & Chromosome instability.read more
Citations
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Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer
Kenneth P. Olive,Michael A. Jacobetz,Christian Davidson,Aarthi Gopinathan,Aarthi Gopinathan,Dominick J.O. McIntyre,Davina J. Honess,Basetti Madhu,Mae A. Goldgraben,Meredith E. Caldwell,David Allard,Kristopher K. Frese,Gina M. DeNicola,Gina M. DeNicola,Christine Feig,Chelsea Combs,Stephen P. Winter,Heather Ireland-Zecchini,Stefanie Reichelt,William J. Howat,Alex R. Chang,Mousumi Dhara,Lifu Wang,Lifu Wang,Felix Rückert,Robert Grützmann,Christian Pilarsky,Kamel Izeradjene,Sunil R. Hingorani,Pearl S. Huang,Susan E. Davies,William Plunkett,Merrill J. Egorin,Ralph H. Hruban,Nigel Whitebread,Karen McGovern,Julian Adams,Christine A. Iacobuzio-Donahue,John R. Griffiths,David A. Tuveson +39 more
TL;DR: Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, it is found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA.
Journal ArticleDOI
Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver
Bruno Costa-Silva,Nicole M. Aiello,Allyson J. Ocean,Swarnima Singh,Haiying Zhang,Basant Kumar Thakur,Basant Kumar Thakur,Annette Becker,Ayuko Hoshino,Milica Tesic Mark,Henrik Molina,Jenny Xiang,Tuo Zhang,Till Martin Theilen,Guillermo García-Santos,Caitlin Williams,Yonathan Ararso,Yujie Huang,Gonçalo Rodrigues,Tang-Long Shen,Knut Jørgen Labori,Inger Marie Bowitz Lothe,Elin H. Kure,Jonathan M. Hernandez,Alexandre Doussot,Saya H. Ebbesen,Paul M. Grandgenett,Michael A. Hollingsworth,Maneesh Jain,Kavita Mallya,Surinder K. Batra,William R. Jarnagin,Robert E. Schwartz,Irina Matei,Héctor Peinado,Ben Z. Stanger,Jacqueline Bromberg,David Lyden,David Lyden +38 more
TL;DR: It is shown that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden and suggests that exosomal MIF primes the liver for metastasis and may be a prognostic marker for the development of PDAC liver metastasis.
Journal ArticleDOI
Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival.
Berna C. Özdemir,Berna C. Özdemir,Tsvetelina Pentcheva-Hoang,Julienne L. Carstens,Xiaofeng Zheng,Chia Chin Wu,Tyler R. Simpson,Hanane Laklai,Hikaru Sugimoto,Hikaru Sugimoto,Christoph Kahlert,Christoph Kahlert,Sergey V. Novitskiy,Ana De Jesus-Acosta,Padmanee Sharma,Pedram Heidari,Umar Mahmood,Lynda Chin,Harold L. Moses,Valerie M. Weaver,Anirban Maitra,James P. Allison,Valerie S. LeBleu,Valerie S. LeBleu,Raghu Kalluri,Raghu Kalluri +25 more
TL;DR: Although myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival, and underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC.
Journal ArticleDOI
Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma.
Paolo P. Provenzano,Carlos Cuevas,Amy Chang,Vikas K. Goel,Daniel D. Von Hoff,Sunil R. Hingorani,Sunil R. Hingorani +6 more
TL;DR: It is shown that systemic administration of an enzymatic agent can ablate stromal HA from autochthonous murine PDA, normalize IFP, and re-expand the microvasculature and in combination with the standard chemotherapeutic, gemcitabine, the treatment permanently remodels the tumor microenvironment and consistently achieves objective tumor responses, resulting in a near doubling of overall survival.
Journal ArticleDOI
Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer
Xiaofeng Zheng,Julienne L. Carstens,Jiha Kim,Matthew Scheible,Judith Kaye,Hikaru Sugimoto,Chia Chin Wu,Valerie S. LeBleu,Raghu Kalluri +8 more
TL;DR: This study functionally probes the role of EMT in PDAC by generating mouse models of PDAC with deletion of Snail or Twist, two key transcription factors responsible for EMT, and highlights the importance of combining EMT inhibition with chemotherapy for the treatment of pancreatic cancer.
References
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Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial.
H. A. Burris,Malcolm J. Moore,J. S. Andersen,M R Green,Mace L. Rothenberg,M R Modiano,M. C. Cripps,Russell K. Portenoy,A M Storniolo,P Tarassoff,R Nelson,F A Dorr,C. D. Stephens,D. D. Von Hoff +13 more
TL;DR: It is demonstrated that gemcitabine is more effective than 5-FU in alleviation of some disease-related symptoms in patients with advanced, symptomatic pancreas cancer and confers a modest survival advantage over treatment with5-FU.
Journal ArticleDOI
Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours
Lawrence A. Donehower,Michele Harvey,Betty L. Slagle,Mark J. McArthur,Charles A. Montgomery,Janet S. Butel,Allan Bradley +6 more
TL;DR: Observations indicate that a normal p53 gene is dispensable for embryonic development, that its absence predisposes the animal to neoplastic disease, and that an oncogenic mutant form of p53 is not obligatory for the genesis of many types of tumours.
Journal ArticleDOI
Genetic instabilities in human cancers
TL;DR: There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels, and recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.
Journal Article
Participation of p53 Protein in the Cellular Response to DNA Damage
TL;DR: A role for the wild-type p53 protein in the inhibition of DNA synthesis that follows DNA damage is suggested and a new mechanism for how the loss of wild- type p53 might contribute to tumorigenesis is suggested.
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