WORLD CLASS BASIC, TRANSLATIONAL AND CLINICAL RESEARCH

Introduction

Understanding how tumour cells signal in a heterogeneous environment

Context is critical for tumour development and response to treatment. It is widely recognised that solid tumours, in addition to the mutated cancer cells, are complex ecosystems encompassing a variety of non-mutated host cells such as immune cells, fibroblasts and endothelial 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 how targeting the microenvironment can be used to overcome resistance to therapies. Due to the complexity of the microenvironment and the cellular interactions, we use a combination of complex in vivo models and reductionist approaches to define the rule set by which individual stromal cell populations regulate tumour cell function.

Using these approaches, we have identified and characterised a number of tumour and stromal-derived signals, which engage tumour cell signalling to promote tumour cell survival, metabolic reviewing and metastasis. Moreover, we have recently identified and characterised stromal fibroblasts with anti-tumour activity, emphasising the complexity of these systems. Thus, tumour cell function is critically dependent on the local milieu and these and other studies emphasise the importance taking the environment into account when devising therapeutic strategies.

Consequently, we also work to develop patient-derived models that recapitulate salient features of the tumour microenvironment. As an example, tumour cells can now be cultured in fully synthetic gels that also support stromal cell co-culture and tuning of the rigidity to accurately recapitulate these features of the tumour environment.

Using these models and approaches we are currently working to determine optimal strategies for therapeutic targeting of the microenvironment.

Selected Publications

Lee BY, Hogg EKJ, Below CR, Kononov A, Blanco-Gomez A, Heider F, Xu J, Hutton C, Zhang X, Scheidt T, Beattie K, Lamarca A, McNamara M, Valle JW, Jørgensen C. (2021)
Heterocellular OSM-OSMR signalling reprograms fibroblasts to promote pancreatic cancer growth and metastasis.
Nature Communication 12(1):7336. PMID: 34921158. PubMed abstract

Below CR, Kelly J, Brown A, Humphries JD, Hutton C, Xu J, Lee BY, Cintas C, Zhang X, Hernandez-Gordillo V, Stockdale L, Goldsworthy MA, Geraghty J, Foster L, O'Reilly DA, Schedding B, Askari J, Burns J, Hodson N, Smith DL, Lally C, Ashton G, Knight D, Mironov A, Banyard A, Eble JA, Morton JP, Humphries MJ, Griffith LG, Jørgensen C. 
A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids.
Nature Materials [Epub 13 September 2021] PMID: 34518665. PubMed abstract

Hutton C, Heider F, Blanco-Gomez A, Banyard A, Kononov A, Zhang X, Karim S, Paulus-Hock V, Watt D, Steele N, Kemp S, Hogg EKJ, Kelly J, Jackstadt RF, Lopes F, Menotti M, Chisholm L, Lamarca A, Valle J, Sansom OJ, Springer C, Malliri A, Marais R, Pasca di Magliano M, Zelenay S, Morton JP, Jørgensen C. (2021)
Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity.
Cancer Cell 39(9):1227-1244.e20. PMID: 34297917 PubMed abstract

Gough RE, Jones MC, Zacharchenko T, Le S, Yu M, Jacquemet G, Muench SP, Yan J, Humphries JD, Jørgensen C, Humphries MJ, Goult BT. (2021)
Talin mechanosensitivity is modulated by a direct interaction with cyclin-dependent kinase-1. 
J Biol Chem. 297(1):100837. PMID: 34118235 PubMed abstract

Pelly VS, Moeini A, Roelofsen LM, Bonavita E, Bell CR, Hutton C, Blanco-Gomez A, Banyard A, Bromley CP, Flanagan E, Chiang SC, Jørgensen C, Schumacher TN, Thommen DS, Zelenay S. (2021)
Anti-Inflammatory Drugs Remodel the Tumor Immune Environment to Enhance Immune Checkpoint Blockade Efficacy.
Cancer Discovery 11(10):2602-2619. PMID: 34031121 PubMed abstract

Wagner MJ, Hsiung MS, Gish GD, Bagshaw RD, Doodnauth SA, Soliman MA, Jørgensen C, Tucholska M, Rottapel R. (2020)
The Shb scaffold binds the Nck adaptor protein, p120 RasGAP, and Chimaerins and thereby facilitates heterotypic cell segregation by the receptor EphB2.
J Biol Chem. 295(12):3932-3944. PMID: 32060095 PubMed abstract

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

Postdoctoral Fellows
Adrian Blanco-Gomez
Celia Cintas
Nasir Haider
Carol McMenemy

Scientific Officers
Xiaohong Zhang
Joanna Kelly

Graduate Students
Catherine Felton
Felix Heider
Louis Roussel

Clinical Fellows
Konstatinos Georgiadis
Seung Hyun Lee