Investigating the impact of TGFβ signalling in the pancreatic cancer microenvironment

Dr Jennifer Morton (CRUK Beatson Institute) http://www.beatson.gla.ac.uk/jeff_evans
Dr Peter Bailey (Cancer Sciences, University of Glasgow)

Pancreatic cancer is a significant health problem and is predicted to become the second most common cause of cancer death by 2025. Survival has remained at a dismal level of less than 5% for the last 50 years, and even now, most therapies are ineffective. Improvements in our understanding of the disease are vital to identify novel targets for therapy.

Pancreatic cancer is renowned for its dense stroma, made up of fibroblasts, immune cells, blood vessels and extracellular matrix proteins such as collagen. The role played by this stroma in driving tumour progression, metastasis and chemo-resistance is currently the subject of much debate. Our recent findings suggest that TGFβ signalling, potentially between tumour and stroma, is key during pancreatic cancer development and progression.

The aim of this project is to investigate the mechanisms by which TGFβ cross-talk between tumour and stroma can drive pancreatic cancer. The student will use cutting-edge transgenic models to investigate the effects of interfering with TGFβ signalling in different cell types within the tumour. The student will also use a variety of ex vivo techniques to identify the targets of these signals that are key players in pancreatic cancer and thus, identify new therapeutic options.

Keywords: Cancer, Pancreas, Microenvironment, Transgenic

References:

Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy (2015)   Miller BW, Morton JP, Pinese M, Saturno G, Marais R, Springer C, Biankin A, Erler JT and Sansom OJ. EMBO Mol Med. 7, 1063-76.

CXCR2 inhibition suppresses acute and chronic pancreatic inflammation   (2015) Steele CW, Karim SA, Foth M, Rishi L, Leach JD, Porter RJ, Nixon C, Jeffry Evans TR, Carter CR, Nibbs RJ, Sansom OJ and Morton JP.   J Pathol. 237, 85-97.

Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles (2015)   Walz S, Lorenzin F, Morton JP, Wiese KE, von Eyss B, Herold S, Rycak L, Dumay-Odelot H, Karim S, Bartkuhn M, Roels F, Wüstefeld T, Fischer M, Teichmann M, Zender L, Wei CL, Sansom O, Wolf E and Eilers M. Nature. 511, 483-7.

Targeting mTOR dependency in pancreatic cancer (2014) Morran DC, Wu J, Jamieson NB, Mrowinska A, Kalna G, Karim SA, Au AY, Scarlett CJ, Chang DK, Pajak MZ, APGI, Oien KA, McKay CJ, Carter CR, Gillen G, Champion S, Pimlott SL, Anderson KI, Evans TR, Grimmond SM, Biankin AV, Sansom OJ and Morton JP. Gut. 63, 1481-9.

Fascin is regulated by slug, promotes progression of pancreatic cancer in mice, and is associated with patient outcomes (2014) Li A, Morton JP, Ma Y, Karim SA, Zhou Y, Faller WJ, Woodham EF, Morris HT, Stevenson RP, Juin A, Jamieson NB, MacKay CJ, Carter CR, Leung HY, Yamashiro S, Blyth K, Sansom OJ, Machesky LM. Gastroenterology. 146, 1386-96.

Periampullary cancers harbor a novel ELF3 tumor suppressor and exhibit genomic properties characteristic of intestinal and pancreatic tumors (2015) Marie-Claude Gingras Gill, Michael M. Ittmann, Chad J. Creighton, Amber L. Johns, Eve Shinbrot, Ninad Dewal, William E. Fisher, Australian Pancreatic Cancer Genome Initiative, Christian Pilarsky, Robert Grüetzmann, Michael J. Overman, Nigel B. Jamieson, George Van Buren, Jennifer Drummond, Kimberly Walker, Oliver A. Hampton, Liu Xi, Donna M. Muzny, Harsha Doddapaneni, Sandra L. Lee, Michelle Bellair, Jianhong Hu, Yi Han, Huyen H. Dinh, Mike Dahdouli, Peter Bailey et al. Cell Reports (accepted for publication).

Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance (2015) Saunus JM, Quinn MC, Patch AM, Pearson JV, Bailey P et al. J Pathol. Jul 14. doi: 10.1002/path.4583. [Epub ahead of print].

Whole–genome characterization of chemoresistant ovarian cancer (2015) Ann-Marie Patch, Elizabeth Christie, Dariush Etemadmoghadam, Dale Garsed, Sian Fereday, Prue Cowin, Joshy George, Kathryn Alsop, Peter Bailey et al. Nature 521, 489–494

Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy (2015) Miller BW, Morton JP, Pinese M, Saturno G, Bailey P et al. EMBO Mol Med. 7, 1063-76.

Whole Genome Sequencing redefines the mutational landscape of Pancreatic Cancer and discovers clinically relevant subtypes (2015) Nicola Waddell, Marina Pajic, Ann-Marie Patch, David K. Chang, Karin S. Kassahn, Peter Bailey et al. Nature 518, 495–501.

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