WORLD CLASS BASIC, TRANSLATIONAL AND CLINICAL RESEARCH

Introduction

Understanding how tumour cells signal in a heterogeneous environment

“Context is everything” is a quote frequently used to highlight how information can be interpreted, or misinterpreted, depending on a particular situation. However, context is also critically important when we consider how cells communicate. It is widely recognised that solid tumours are complex ‘organs’, which contain a number of non-mutated host cells such as immune cells, fibroblasts and endothelial cells in addition to the mutated cancer cells. This is particularly prominent in pancreatic ductal adenocarcinoma – where up to 80% of the tumour volume is made up by the tumour stroma (host cells and fibrosis). The microenvironment influence how tumour cells progress and respond to therapeutic intervention, however the mechanisms for this is not well described.

In the Systems Oncology laboratory, we are focused on determining how tumour cells exchange information with host cells to support tumour growth and resistance to therapies. Specifically, we have developed methods to differentially label tumour and host cells, such that we can co-culture these and determine how information is exchanged using proteomics. Recently, we applied these technologies to study how expression of the most frequently mutated oncogene (KRAS) in tumour cells initiates a signal (SHH), which co-opt resident fibroblasts. Co-opted fibroblasts secrete a number of signals following response to SHH, some of which (IGF1 and GAS6) initiate reciprocal signalling in the KRAS-expressing tumour cells. Importantly, while mutated KRAS can activate signalling through specific pathways (such as the MAPK pathway) in a cell autonomous manner, signalling through other pathways (such as AKT pathway) is strictly dependent on reciprocal signals from co-opted fibroblasts. This is important because tumour cells alter their metabolism and ability to apoptose under these conditions, and consequently, reciprocal signals should be co-targeted to efficiently kill these tumour cells.  

Selected Publications

Tape CJ, Ling S, Dimitriadi M, McMahon KM, Worboys JD, Leong HS, Norrie IC, Miller CJ, Poulogiannis G, Lauffenburger DA, Jørgensen C. (2016)
Oncogenic KRAS regulates tumor cell signaling via stromal reciprocation.
Cell 165(4) 910-920. PubMed abstract

Locard-Paulet M, Lim L, Veluscek G, McMahon K, Sinclair J, van Weverwijk A, Worboys JD, Yuan Y, Isacke CM, Jørgensen C. (2016)
Phosphoproteomic analysis of interacting tumor and endothelial cells identifies regulatory mechanisms of transendothelial migration.
Science Signaling 9(414):ra15. PubMed abstract

So J, Pasculescu A, Dai AY, Williton K, James A, Nguyen V, Creixell P, Schoof EM, Sinclair J, Barrios-Rodiles M, Gu J, Krizus A, Williams R, Olhovsky M, Dennis JW, Wrana JL, Linding R, Jorgensen C, Pawson T, Colwill K. (2015)
Integrative analysis of kinase networks in TRAIL-induced apoptosis provides a source of potential targets for combination therapy.
Science Signaling 8(371):rs3. PubMed abstract

Tape CJ, Worboys JD, Sinclair J, Gourlay R, Vogt J, McMahon KM, Trost M, Lauffenburger DA, Lamont DJ, Jørgensen C. (2014)
Reproducible automated phosphopeptide enrichment using magnetic TiO2 and Ti-IMAC.
Analytical Chemistry 86(20):10296-302. PubMed abstract

Worboys JD, Sinclair J, Yuan Y, Jørgensen C. (2014)
Systematic evaluation of quantotypic peptides for targeted analysis of the human kinome.
Nature Methods 11(10):1041-4. PubMed abstract

Tape CJ, Norrie IC, Worboys JD, Lim L, Lauffenburger DA, Jørgensen C. (2014)
Cell-specific labeling enzymes for analysis of cell-cell communication in continuous co-culture.
Molecular & Cellular Proteomics 13(7):1866-76. PubMed abstract

Anton KA, Sinclair J, Ohoka A, Kajita M, Ishikawa S, Benz PM, Renne T, Balda M, Jørgensen C, Matter K, Fujita Y. (2014)
PKA-regulated VASP phosphorylation promotes extrusion of transformed cells from the epithelium.
Journal of Cell Science 127(Pt 16):3425-33. PubMed abstract

Girotti MR, Pedersen M, Sanchez-Laorden B, Viros A, Turajlic S, Niculescu-Duvaz D, Zambon A, Sinclair J, Hayes A, Gore M, Lorigan P, Springer C, Larkin J, Jorgensen C, Marais R. (2013)
Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma.
Cancer Discovery (2):158-67. PubMed abstract

Jørgensen C, Sherman A, Chen GI, Pasculescu A, Poliakov A, Hsiung M, Larsen B, Wilkinson DG, Linding R, Pawson T. (2009)
Cell-specific information processing in segregating populations of Eph receptor-ephrin-expressing cells.
Science 326(5959):1502-9. PubMed abstract

Chang Q, Jørgensen C, Pawson T, Hedley D. (2008)
Effects of dasatinib on EphA2 receptor tyrosine kinase activity and downstream signaling in pancreatic cancer.
British Journal of Cancer 99(7):1074-82. PubMed abstract