SPARC dependent collagen deposition and gemcitabine delivery in a genetically engineered mouse model of pancreas cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterised by extensive matrix deposition that has been implicated in impaired drug delivery and therapeutic resistance. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that regulates collagen deposition and is highly upre...

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Bibliographic Details
Published in:EBioMedicine 2019-10, Vol.48, p.161-168
Main Authors: Ramu, Iswarya, Buchholz, Sören M., Patzak, Melanie S., Goetze, Robert G., Singh, Shiv K., Richards, Frances M., Jodrell, Duncan I., Sipos, Bence, Ströbel, Philipp, Ellenrieder, Volker, Hessmann, Elisabeth, Neesse, Albrecht
Format: Article
Language:English
Subjects:
Animals
Antimetabolites, Antineoplastic - pharmacology
Antimetabolites, Antineoplastic - therapeutic use
Cell Line, Tumor
Chemoresistance
Collagen
Collagen - metabolism
Deoxycytidine - analogs & derivatives
Deoxycytidine - pharmacology
Deoxycytidine - therapeutic use
Disease Models, Animal
Disease Progression
Drug delivery
Gemcitabine
Gene Expression Regulation, Neoplastic
Humans
Mice
Mice, Transgenic
Osteonectin - genetics
Osteonectin - metabolism
Pancreatic cancer
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - etiology
Pancreatic Neoplasms - metabolism
Research paper
SPARC
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Summary:Pancreatic ductal adenocarcinoma (PDAC) is characterised by extensive matrix deposition that has been implicated in impaired drug delivery and therapeutic resistance. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that regulates collagen deposition and is highly upregulated in the activated stroma subtype with poor prognosis in PDAC patients. KrasG12D;p48-Cre;SPARC−/− (KC-SPARC−/−) and KrasG12D;p48-Cre;SPARCWT (KC-SPARCWT) were generated and analysed at different stages of carcinogenesis by histological grading, immunohistochemistry for epithelial and stromal markers, survival and preclinical analysis. Pharmacokinetic and pharmacodynamic studies were conducted by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and immunohistochemistry following gemcitabine treatment (100 mg/kg) in vivo. Global genetic ablation of SPARC in a KrasG12D driven mouse model resulted in significantly reduced overall and mature collagen deposition around early and advanced pancreatic intraepithelial neoplasia (PanIN) lesions and in invasive PDAC (p 
ISSN:2352-3964
2352-3964
DOI:10.1016/j.ebiom.2019.09.024