Nuclear function and metabolism in cancer pathogenesis
Samantha Dickson Brain Cancer Unit
Professor Paolo Salomoni
The main focus of my group is on molecular mechanisms underlying cell fate control in normal and neoplastic stem cells, and how alterations of these mechanisms contribute to cancer in the brain and other tissues. In particular, we have investigated two main processes involved in tumourigenesis: i) alteration of chromatin function and the interchromatin space; ii) metabolic deregulation.
Chromatin function and the interchromatin space
Our long-standing interest is in the nuclear factor Promyelocytic Leukaemia protein (PML), which is inactivated in acute promyelocytic leukaemia (APL) and the essential component of a subnuclear structure of the interchromatin space called the PML-nuclear body (PML-NB; Figure 1). We found that PML regulates stem cell fate during central nervous system (CNS) development at least in part by targeting the tumour suppressor retinoblastoma to PML-NBs (Regad et al., Nat Neurosci 2009). Our ongoing work implicates PML in regulation of neurogenesis and neoplastic transformation in the postnatal brain as well as in the peripheral nervous system (unpublished).
We then turned our attention to a PML-interacting protein, called DAXX, which acts as chaperone for the histone variant H3.3. Remarkably, driver mutations in the H3.3 genes are found in paediatric glioblastoma multiforme (GBM), the first cause of cancer death in children, and in bone cancer. Furthermore, H3.3 loading machinery is affected by the APL oncogene PML-RARalpha. The identification of histone mutations in human cancer represents a paradigm shift in our understanding of cancer epigenetics.
We were first to implicate H3.3 loading in regulation of chromatin remodelling and transcription in the CNS and revealed a novel regulatory mechanism controlling H3.3 deposition downstream calcium signalling (Michod et al., Neuron 2012; Figure 2).
We have recently been awarded funding from the European Research Council, Brain Tumour Charity, Medical Research Council, Association for International Cancer Research and Biomedical Research Centre/National Institute for Health Research to study the role and regulation of histone variant loading in cancer pathogenesis (bone cancer work conducted jointly with Adrienne Flanagan, UCL-CI).
Figure 1 (left panel). PML (red) is found in PML-Nuclear Bodies in neural progenitor cells in the developing cerebellum (postnatal day 7). Nuclei are stained with DAPI (blue).
Figure 2 (right panel). The histone H3.3 is a replication-independent variant of histone 3 implicated in pathogenesis of brain and bone tumours. We were first to show the involvement of H3.3 in regulation of transcription in the central nervous system. For more information: Michod et al., Neuron 2012.
The other focus of my lab is on metabolism deregulation in cancer. We focus on a metabolic pathway called autophagy and its role in cancer development. Our work has shown that autophagy plays an important role in regulation of survival in leukaemic stem cells and of migration/invasion in brain cancer stem cells (Bellodi et al., J Clin Invest 2009; Galavotti et al., Oncogene 2013; Figure 3). This work has led to three clinical trials for the use of autophagy inhibitors in cancer therapy - clinical leads for the three trials are: Tessa Holyoake, Glasgow (Chronic Myeloid Leukaemia); Susan Short, Leeds (GBM); Ming Lee, UCL (lung cancer). We are also investigating the role of mitochondrial dysfunction in regulation of neural stem cell fate and tumourigenesis in the brain.
Critically, recent funding awarded to the laboratory will allow us to explore the interaction between metabolism and nuclear function in cancer pathogenesis.
Figure 3. Autophagy regulates invasion and the response to cancer therapy (targeted therapy and genotoxic stress). Autophagy can be inhibited pharmacologically by chloroquine and hydroxychloroquine.
- Julia Hofmann (postdoc)
- Manav Pathania (postdoc)
- Ana Paula Leite (postdoc)
- Valeria Amodeo (postdoc)
- Aikaterini Lampada (PhD student)
- Angela Swampillai (PhD student)
- A Deli (PhD student)
- Nicola Maestro (technician)
Salomoni P. The PML-interacting protein DAXX: histone loading gets into the picture. Front Oncol 2013 3:152.
Michod D, Bartesaghi S, Khelifi A, Bellodi C, Nicotera P, Salomoni P. Calcium-dependent dephosphorylation of the histone chaperone DAXX regulates H3.3 loading and transcription upon neuronal activation. Neuron 2012 74:122-135.
Galavotti S, Bartesaghi S, Faccenda D, Shaked-Rabi M, Sanzone S, McEvoy A, Dinsdale D, Condorelli F, Brandner S, Campanella M, Grose R, Jones C, Salomoni P. The autophagy-associated factors DRAM1 and p62 regulate cell migration and invasion in glioblastoma stem cells. Oncogene 2013 32:699-712.
Regad T, Bellodi C, Nicotera P, Salomoni P. The tumor suppressor Pml regulates cell fate in the developing neocortex. Nat Neurosci 2009 12:132-140. online
Bellodi C*, Lidonnici MR*, Hamilton A*, Vignir Helgason G, …, Salomoni P*, Calabretta B* (*equal contribution). Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells including primary CML stem cells. J Clin Invest 2009 119:1109-1123.
A full list is here.