MedicalResearch.com Interview with:
Dr Angus Cameron
Kinase Biology Laboratory
Barts Cancer Institute at Queen Mary University of London and
Professor Peter Parker
Protein Phosphorylation Laboratory
The Francis Crick Institute
Medical Research: What is the background for this study? What are the main findings?
Response: A particular family of candidate targets for cancer therapies (the three members of the protein kinase, or PKN, family) have been largely overlooked in terms of our understanding of their roles in normal biology and also in disease.
Since any programme to develop new treatments is well informed by understanding the normal roles of the drug targets in non-tumour settings, our research teams ‘knocked-out’ these genes in a model mammalian system, in mice, and observed the effect.
A key finding is that whilst two of the protein kinases, PKN1 and PKN3, are not necessary for mammalian development or adulthood, for PKN2 there is an absolute requirement in embryo development, but evidence of little requirement in adulthood.
Our teams then analysed in some detail the genetics and pathology of the developmental defects for PKN2 knock-outs. This established the importance of PKN2 in mesenchymal cell survival and proliferation during development. Mesenchymal cells are dynamic contractile cells which provide structure and shape to the developing embryo. This finding has profound effects on multiple developmental events. Mesenchymal cells are also important in many connective tissue conditions, including fibrosis of the lungs, and in cancer where mesenchymal cells can support invasion of cancer cells into tissues.
Medical Research: What should clinicians and patients take away from your report?
Response: There’s a limited need for the protein kinases in adulthood. As they are candidate targets in multiple cancers, this provides strong support to elaborate a drug development programme against these proteins.
Medical Research: What recommendations do you have for future research as a result of this study?
Response: We need to understand what specific roles these proteins play in cancer pathology and our mouse models provide the opportunity to do this. Evidence indicates that there are altered expression patterns associated with tumours and this might indicate some properties that are specific to tumour cells. However, the developmental role of PKN2 also prescribes analysis of the role of this family in the tumour microenvironment where connective ‘stromal’ tissue plays such an important role in tumour development and immune suppression.
Ivan Quétier, Jacqueline J.T. Marshall, Bradley Spencer-Dene, Sylvie Lachmann, Adele Casamassima, Claudio Franco, Sarah Escuin, Joseph T. Worrall, Priththivika Baskaran, Vinothini Rajeeve, Michael Howell, Andrew J. Copp, Gordon Stamp, Ian Rosewell, Pedro Cutillas, Holger Gerhardt, Peter J. Parker, Angus J.M. Cameron. Knockout of the PKN Family of Rho Effector Kinases Reveals a Non-redundant Role for PKN2 in Developmental Mesoderm Expansion. Cell Reports, 2016;
Dr Angus Cameron and, & Professor Peter Parker (2016). Separate Roles For Protein Kinases in Embryo Development and Cancer