Last month, the Third Crick Symposium was held in London (UK), with the aim of discussing ways in which basic biological research could progress from “Genetics to molecules to therapies”. In particular, this meeting brought together chemists, biologists and clinicians from what will be the new Francis Crick Institute in London, which is scheduled to open in 2015.
Of note, Professor Charles Swanton (CRUK London Research Institute and UCL Cancer Institute, UK) described four cases of intra-tumour heterogeneity in metastatic renal cell carcinoma (RCC). These findings demonstrated that certain mutations were ubiquitous, shared or unique within specific regions of the metastatic RCC (Gerlinger et al., 2012). For example, using exome sequencing, chromosome aberration analysis and DNA ploidy profiling it was noted that VHL was mutated in all analysed tumour regions within one patient. An activating mutation in mammalian target of rapamycin (mTOR) was also observed in all but one primary tumour region. However, there were distinct SETD2 and KDM5C mutations present within the primary and metastatic regions of the RCC, and these genes have been previously discussed here. This study by Gerlinger et al. highlights that a single biopsy may not represent the mutational load within a tumour, and that certain tumour cell populations may react differently to treatments. Accordingly, therapies which target ubiquitous mutations may prove to be more successful. It would be particularly interesting to see if there is similar intra-tumour heterogeneity within BHD-associated RCCs, as alluded to in this earlier blog post.
The FLCN-associated signalling diagram and the work described above underlines the importance of mTOR complex (mTORC) signalling in the development of RCC. Thus in mid-March, we attended a set of “Talks about TORCs” organised by the Biochemical Society in London. Recent advances in TOR signalling were shared and its role in a variety of processes was introduced. For example, the first talk by Professor Michael Hall (University of Basel, Switzerland) discussed TOR signalling in relation to growth and metabolism. Notably, Professor Hall suggested that mammalian TOR should be renamed mechanistic TOR, as the pathway is not unique to mammals. This was aptly demonstrated by Dr Miguel Navarro (Institute of Parasitology and Biomedicine “López-Neyra”, Spain) with his work on TOR signalling in Trypanosoma brucei (Barquilla et al., 2012). In addition, Professor Thomas Weichhart (Medical University of Vienna, Austria) and Professor Doreen Cantrell (University of Dundee, UK) introduced the role of mTOR signalling in immunity, which is of interest as FLCN/FNIP1 may be associated with B-cell development (as discussed here and here). Professor Linda Partridge (UCL, UK) also introduced the connection between mTOR signalling and ageing. This is especially relevant as recent work has connected FLCN with longevity in C. elegans (Gharbi et al., 2013), which will be discussed in our BHD Research Blog soon. Moreover, Dr Andrew Tee presented his work on ULK1 and mTOR signalling (Dunlop et al., 2011), as well as a poster on BHD. For more information regarding the work of Dr Tee, please look at our lab profile here.
Finally, do visit our Conferences and Events page to keep updated with meetings that are of relevance to BHD syndrome. In particular, the Fifth BHD Symposium and Second HLRCC Symposium will be held in Paris on 28-29th June 2013, and the abstract and earlybird registration deadline is 15th April 2013.
- Barquilla, A., Saldivia, M., Diaz, R., Bart, J., Vidal, I., Calvo, E., Hall, M., & Navarro, M. (2012). Third target of rapamycin complex negatively regulates development of quiescence in Trypanosoma brucei Proceedings of the National Academy of Sciences, 109 (36), 14399-14404 DOI: 10.1073/pnas.1210465109
- Dunlop EA, Hunt DK, Acosta-Jaquez HA, Fingar DC, & Tee AR (2011). ULK1 inhibits mTORC1 signaling, promotes multisite Raptor phosphorylation and hinders substrate binding. Autophagy, 7 (7), 737-47 PMID: 21460630
- Gerlinger, M., Rowan, A., Horswell, S., Larkin, J., Endesfelder, D., Gronroos, E., Martinez, P., Matthews, N., Stewart, A., Tarpey, P., Varela, I., Phillimore, B., Begum, S., McDonald, N., Butler, A., Jones, D., Raine, K., Latimer, C., Santos, C., Nohadani, M., Eklund, A., Spencer-Dene, B., Clark, G., Pickering, L., Stamp, G., Gore, M., Szallasi, Z., Downward, J., Futreal, P., & Swanton, C. (2012). Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing New England Journal of Medicine, 366 (10), 883-892 DOI: 10.1056/NEJMoa1113205
- Gharbi, H., Fabretti, F., Bharill, P., Rinschen, M., Brinkkötter, S., Frommolt, P., Burst, V., Schermer, B., Benzing, T., & Müller, R. (2013). Loss of the Birt-Hogg-Dubé gene product Folliculin induces longevity in a hypoxia-inducible factor dependent manner Aging Cell DOI: 10.1111/acel.12081