Systems Oncology - Claus Jørgensen

Claus Jørgensen obtained his BSc in Biochemistry and Molecular Biology at the University of Southern Denmark, Odense Denmark in 1999. At the same University, he later received his PhD in 2005. His first Post Doctoral position took him to Toronto, Canada, and the Samuel Lunenfeld Research Institute, under the guidance of Professor Tony Pawson. It was during his four-year training with Prof Pawson that he developed a keen interest in reciprocal signalling. In 2010, Claus moved to The Institute of Cancer Research, London, to lead the Cell Communication Team. Here, he focused on using and further developing an experimental platform to interrogate heterotypic cell signalling and its impact on tumour formation and progression. In 2011, Claus was awarded a CRUK Career Development Award. He joined the CRUK Manchester Institute in early 2014 to form the Systems Oncology group, which will focus on the complex interactions between malignant and normal cells, with a particular interest in pancreatic cancer. In 2017 Claus was awarded an ERC Consolidator Grant.

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.

Synthetic hydrogel models for co-culture and analysis of primary tumour and stromal cells.

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.

Overview

 

Tumours are complex ecosystems where cancer cells are embedded within a complex stromal microenvironment, comprising multiple infiltrating cell types and pathological changes to the extracellular matrix. The aim of the Systems Oncology laboratory is to determine and define how tumour cells conscribe host cells to support tumour development and resistance to therapies. Understanding these rules will enable the development of rational combination therapies targeting both tumour cell intrinsic dependencies as well as their extrinsic dependencies on stromal reciprocal signals.

Pancreatic Ductal Adenocarcinoma

 

Pancreatic Ductal Adenocarcinoma (PDA) is a dismal disease with an average five-year survival rate of 9%. PDA is the 11th most common cancer in the UK but the fourth largest contributor to cancer related deaths. PDA is characterised by an extensive desmoplastic reaction, which makes up 80% of the tumour volume on average. Here, an abundant and pathological remodelled extracellular matrix increases tissue stiffness and interstitial pressure, which results in decreased therapeutic efficiency. Moreover, the microenvironment contains an abundant fibroblast and myeloid cell infiltrate, which reduces immune surveillance and confers resistance to therapy.

Figure 1: Pancreatic cancer organoids (purple) were co-cultured with pancreatic fibroblasts (green) and bone-marrow derived macrophages (orange) in a synthetic PEG hydrogel scaffold.

 

Mapping the tumour microenvironment of PDA

The tumour microenvironment of PDA has been ascribed with both tumour promoting and tumour restrictive abilities. Stromal targeted therapies should therefore aim to inhibit the tumour promoting effects of the stroma while augmenting the tumour restrictive effects. We developed mass cytometry antibody panels recognising cell surface receptors and used this to assign subsets of cancer-associated fibroblasts (CAFs) and immune cells in tumours isolated from a genetic engineered mouse model of PDA. We observed that PDA tumours contains two separate populations of CAFs distinguished by the expression of CD105 (Endoglin). Isolation and characterisation of both CD105pos and CD105neg CAF revealed distinct expression of immune-regulatory signals.

Moreover, the two stromal subsets expressed CD105 in a noninterchangeable manner and responded differentially to most exogenous signals tested, suggesting the subsets may have distinct functional roles in the tumour microenvironment. Indeed, tumour cells co-implanted with CD105pos fibroblasts grew similarly to tumour cells implanted in isolation, suggesting a tumour permissive role of CD105pos fibroblast. In contrast, co-implanted CD105neg fibroblasts restrict tumour growth, which was dependent on functional adaptive immunity. These data demonstrate that tumour promoting and tumour restrictive fibroblast subsets co-exist in the pancreas and provide molecular insights into the signals governing tumour development.

 

Development of a fully synthetic 3D model of human pancreatic cancer

 

Although tumour cells constitute less than 20% of the tumour volume in patients, most in vitro models do not support the study of tumour cells within an equally complex microenvironment. To improve how tumours can be modelled in vitro, we worked with Prof Linda Griffith (MIT) and Prof Martin Humphries (UoM) to adapt a fully synthetic scaffold to support growth of both tumour and stromal cells. Peptide ligands were used to mimic the adhesive signals found in the tumour microenvironment of pancreatic cancer, which enabled growth of both normal and tumour cells. Moreover, tumour cells grown in these scaffolds produce their own extracellular matrix, which we found engage integrin ligands in a similar manner to what is observed in vivo. Due to the synthetic nature of these scaffolds, they can be modified to recapitulate the entire stiffness range of patient tumours. We observe that tumour cells exhibit a different growth pattern and signalling depending on the scaffold stiffness, suggesting that incorporation of these models will be important to further address the impact of the environment on tumour cell function and to functionally interrogate stromal targeted therapies in patient derived models.

 

Tumour stromal interactions control tumour growth and metastasis

 

Tumour cells co-opt stromal cells to secrete signals, which in turn expand the signalling network tumour cells can engage. Due to the complexity of the tumour microenvironment, we interrogated how stromal reciprocal signals depend on the stromal cellular composition. Interestingly, stromal fibroblasts behave in a highly adaptive manner to change the secreted signals depending on the cellular composition. Specifically, tumour cell secreted GM-CSF induces macrophages to secrete Oncostatin M (OSM), which in turn induce fibroblasts to produce multiple pro-tumorigenic inflammatory signals. This ensuing signalling environment induce a more mesenchymal tumour cell phenotype. Consequently, blocking OSM signalling in vivo reduce tumour growth and metastasis.

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

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