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2012 © Institute for Molecular Medicine Finland FIMM

Lung cancer model systems

Research Overview

We study the cell biological and biochemical properties of key lung cancer tumour suppressors, and integrate this knowledge to build better in vivo and ex vivo lung cancer models to investigate their function in complex microenvironments. Our long-term aim is to investigate new strategies for intervention in lung cancer progression.

Background

Lung cancer is the leading cause of cancer-related mortality worldwide, yet traditional chemotherapy and surgery are still the most effective treatments currently available. Personalised medicine approaches to lung cancer face big challenges: diagnoses are typically made when the disease is already metastatic, and cancer cell populations are notably heterogeneous, complicating molecular profiling. New methods to study the causes of lung cancer and inform the design of novel treatment options are therefore of crucial importance.

Strategy

Our research strategy comprises highly specific protein purification methods to define protein molecular networks, combined with cell biological assessment of protein localisation and function in vitro and in vivo. We apply reverse genetics approaches on sets of candidate lung cancer tumour suppressors. Research angles are pursued in a diverse set of systems, from human cells to mice to complex epithelial culture systems. To translate our findings to the clinic, key findings in animal models will be aligned with primary lung cancer patient materials, integrating biobanking and molecular profiling capacities available at FIMM and associated Biocenters. We work together with industry partners to develop complex models for target validation and gene therapy approaches via active participation in the European public-private IMI consortium PREDECT (http://predect.eu).

Projects

Contribution of EphA3 gene mutation to lung cancer progression

We are studying how mutations in the EPHA3 receptor tyrosine kinase gene, which are frequently detected in human lung adenocarcinomas, promote cancer formation. Through generation of a series of cell lines that express tagged forms of human lung cancer-associated variants, we showed that point mutations lead to a decrease in receptor function, consistent with a putative tumour suppressor function. Given the known role of Eph receptor family signalling in controlling cell shape and cell-cell contact-based repulsion, we are now pursuing studies to address its function in appropriate mouse models. To find how loss of EphA3 function affects cancer formation, we obtained EphA3 null animals from our collaborators, which are utilised for lung cancer susceptibility studies. We also pursue ways to integrate clinical profiling of EphA3 mutant human adenocarcinomas, and assess receptor signalling profiles to ask how defective EphA3 signalling could modulate receptor crosstalk and thereby affect migration decisions.

Generation of somatic lung cancer models

We are developing strategies to generate somatic mouse models of lung cancer, using viral delivery to the lung epithelium of adult mice expressing conditional forms of non-small cell lung cancer-associated tumour suppressors or oncogenes. Through combining germ-line conditional mutations (activated by Cre) with lentiviral vectors carrying shRNAs against (putative) tumour suppressors or oncogenic cDNAs, we aim to develop a strategy for rapid and versatile assessment of biological events contributing to lung cancer pathology and therapeutic response. We have now also begun a collaboration with the Kainov group at FIMM to extend our approaches to include an attenuated strain of influenza A virus as a vehicle for targeting the upper respiratory tract and lung. Part of these studies are executed within the context of the PREDECT IMI Consortium, a pre-competitive partnership with 7 EU pharma (including AstraZeneca, Roche and Orion), aiming to build sufficiently complex low-throughput models of breast, prostate and lung cancer to ameliorate target validation. The PREDECT project aims to comprehensively model the circuitry of parallel culture modules before and after cancer target perturbation, and to attempt its comparison with human cancer pathology. This will inform the design of optimal preclinical models representative of patient cohorts.

http://www.predect.eu/

Role of Hippo pathway kinases in epithelial cell proliferation

The mammalian Hippo tumour suppressor pathway is frequently switched off in various cancers, including the lung. Hippo kinase signalling conveys architectural cues from the cell membrane to the transcriptional machinery. We wish to find out how its core kinases, LATS1 and LATS2, affect cell division in culture models with different architectural compositions. To this end, we are studying how cellular localisation of these proteins correlates with their function.

About Emmy Verschuren

Emmy received her undergraduate degree in 1997 from the University of Groningen in the Netherlands. She started graduate work in the lab of Nic Jones at the ICRF (CRUK), London, exploring mechanisms of cell death triggered by the Kaposi’s sarcoma-associated herpesvirus cyclin, K cyclin. She continued this graduate work in the lab of Gerard Evan at UCSF, San Francisco, investigating in vitro and in vivo oncogenic activities of K cyclin. After obtaining her Ph.D. in 2003, she began a postdoc with Peter Jackson at Stanford University for which she was awarded a Damon Runyon Fellowship. She here studied cell cycle control imposed by the Emi1 protein, an inhibitor of the Anaphase-Promoting Complex/Cyclosome ubiquitin ligase, and revealed a protein stabilization/mRNA expression circuit that maintains DNA integrity and prevents cellular senescence. She moved with Peter Jackson to Genentech Inc., South San Francisco, where her efforts included the discovery of putative tumour suppressors via a high-throughput senescence screen.

Selected Publications:

1. Peart, M.J., Pyurovsky, M.V., Ulrist M., Verschuren, E.W., Jackson, P.K. and Prives, C. (2010). APC/CCdc20 targets E2F1 for degradation in prometaphase. Cell Cycle. 9: 3956-64.

2. Verschuren, E.W., Ban, K.H., Masek, M.A., Lehman, N.L. and Jackson, P.K.(2007). Loss of Emi1-dependent APC/C inhibition deregulates E2F target expression and elicits DNA damage-induced senescence. Mol. Cell. Biol. 27: 7955-65.

3. Verschuren E.W. and Jackson, P.K. (2007). Putting transcription repression and protein destruction in pRb’s pocket. Review. Dev. Cell. 12: 169-70.

4. Lehman, N.L., Verschuren, E.W., Hsu, J.Y., Cherry, A.M. and Jackson, P.K. (2006). Overexpression of the anaphase promoting complex/cyclosome inhibitor Emi1 leads to tetraploidy and genomic instability of p53-deficient cells. Cell Cycle. 5: 1569-73.

5. Marangos P., Verschuren E.W., Chen, R., Jackson P.K. and Carroll, J. (2007). Emi1-mediated regulation of the APC controls timing of progression through meiosis in mouse oocytes. J. Cell. Biol.176: 65-75.

6. Eldridge, A.G., Loktev, A.V., Hansen, D.V., Verschuren, E.W., Reimann, J.D. and Jackson, P.K. (2006). The evi5 oncogene regulated cyclin accumulation by stabilizing the anaphase-promoting complex inhibitor Emi1. Cell. 124: 367-380.

7. Christophorou, M.A., Martin-Zanca, D., Soucek, L., Lawlor, E.R., Brown-Swigart, L., Verschuren, E.W. and Evan, G.I. (2005). Temporal dissection of p53 function in vitro and in vivo. Nat. Genet. 37: 718-26.

8. Verschuren, E.W., Hodgson, J.G., Gray, J.W., Kogan, S., Jones, N. and Evan, G.I. (2004). The role of p53 in suppression of KSHV cyclin-induced lymphomagenesis. Cancer Res., 64: 581-589.

9. Verschuren, E.W., Klefstrom, J., Evan, G.I. and Jones, N. (2002). The oncogenic potential of Kaposi’s sarcoma-associated herpesvirus cyclin is exposed by p53 loss in vitro and in vivo. Cancer Cell, 2:229-241.

Group Members

Funding

Orion-Farmos Research Foundation

Prospective Group Members:

We are always interested to receive inquiries from talented postdocs, PhD or undergraduate students to work in our group. Please send your inquiry (including CV, list of publications, contact info of 3 references, and cover letter describing your long-term research ambitions) to emmy.verschuren@helsinki.fi.