WORLD CLASS BASIC, TRANSLATIONAL AND CLINICAL RESEARCH

Introduction

Understanding how tumour cells signal in a heterogeneous environment

“Context is everything” is a quote used to emphasise how particular situations form our understanding of information. Similarly, context is critical for tumour development and response to treatment. It is widely recognised that solid tumours are complex ecosystems encompassing a variety 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 80% of the tumour volume, on average, is made up by the tumour stroma (host cells and fibrosis).

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. Due to the complexity of the microenvironment and the cellular interactions, we use reductionists approaches to define the rule set by which individual stromal cell populations regulate tumour cell function, before testing these observations in more complex settings.  As an example, using differentially labelled tumour and host fibroblasts, we recently detailed how information is exchanged using proteomics. Specifically, we described how expression of the most frequently mutated oncogene (KRAS) in tumour cells initiates a signal (SHH), which instructs fibroblasts to initiate reciprocal signalling leading to activation of signalling pathways beyond those regulated by oncogenic KRAS in the tumour cells. This is important because fibroblast signalling instructs tumour cells to alter their metabolism and decrease apoptosis under these conditions. Consequently, we hypothesise that reciprocal signals should be co-targeted to efficiently kill these tumour cells.

Selected Publications

Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, Fearon D, Greten FR, Hingorani SR, Hunter T, Hynes RO, Jain RK, Janowitz T, Jorgensen C, Kimmelman AC, Kolonin MG, Maki RG, Powers RS, Puré E, Ramirez DC, Scherz-Shouval R, Sherman MH, Stewart S, Tlsty TD, Tuveson DA, Watt FM, Weaver V, Weeraratna AT, Werb Z. (2020)
A framework for advancing our understanding of cancer-associated fibroblasts
Nat Rev Cancer. 20(3):174-186. PMID 31980749 PubMed abstract

Chastney MR, Lawless C, Humphries JD, Warwood S, Jones MC, Knight D, Jorgensen C, Humphries MJ. (2020)
Topological features of integrin adhesion complexes revealed by multiplexed proximity biotinylation. 
Journal of Cell Biology 219(8):e202003038. PubMed abstract

Kershaw S, Morgan DJ, Boyd J, Spiller DG, Kitchen G, Zindy E, Iqbal M, Rattray M, Sanderson CM, Brass A, Jorgensen C, Hussell T, Matthews LC, Ray DW. (2020)
Glucocorticoids rapidly inhibit cell migration through a novel, non-transcriptional HDAC6 pathway. 
Journal of Cell Science 133(11):jcs242842. PubMed abstract

Tape CJ, Jørgensen C. (2017)
Cell-specific labeling for analyzing bidirectional signaling by mass spectrometry.
Methods in Molecular Biology 1636:219-234. PubMed abstract

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

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

Postdoctoral Fellows
Adrian Blanco-Gomez
Nasir Haider
Celia Cintas
Alexander Kononov
Stephen Kershaw

Scientific Officers
Xiaohong Zhang
Joanna Kelly

Graduate Students
Catherine Felton
Felix Heider

Clinical Fellow
Konstatinos Georgiadis