Paola Scaffidi: Projects

Findings over the past 10 years have strongly implicated deregulation of epigenetic instructions in cancer. Epigenetic alterations in chromatin and DNA methylation are universal features of neoplasia and recurrent mutations in proteins involved in epigenetic control are increasingly identified in various cancers.

Thanks to the blossoming of genome-wide approaches, comprehensive epigenetic profiles of various cancer types are being generated. Despite major advances in the field of cancer epigenetics, however, discriminating between 'driver' epigenetic alterations, which play critical roles in cancer development, and 'passenger' epigenetic changes, which simply occur as consequence of altered cell function, remains often challenging. This is partially due to the fact that traditional bulk approaches analyse tumours in their entirety and disregard intratumour heterogeneity. 

CSCs have recently emerged as a critical subset of cancer cells which play key roles in the initiation and maintenance of various types of cancers. Being the cells that sustain the long-term growth of tumours, CSCs promise to be critical therapeutic targets with the potential of revolutionising cancer treatment. Remarkably little, however, is known about their biological properties and the mechanisms through which they maintain tumour growth. Our studies aim at identifying functionally important epigenetic features that define human CSCs.

While various types of cancers differ in many aspects, basic principles such as loss of cell identity, acquisition of uncontrolled self-renewal and generation of functionally heterogeneous populations of cancer cells are common events always associated with neoplasia. Epigenetic mechanisms are likely to be critical players in these processes and a better understanding of how they control CSC formation and function may lay the foundation for the development of more effective strategies of therapeutic intervention.

Figure 1

Figure 1. Epigenetic heterogeneity of cancer cells. Tumours comprise phenotypically and functionally diverse cell types. Histone modifications, DNA methylation, and higher-order chromatin structure define the epigenetic status of CSCs and contribute to the maintenance of CSC properties. The tumour bulk arises through differentiation of CSCs into heterogeneous cell types, characterized by various epigenetic states that activate or silence distinct sets of genes. Changes in the epigenetic landscape occur during differentiation and are associated with loss of self-renewal and tumorigenicity. (Click to view larger image)

We have recently shown that cells with functional hallmarks of CSCs can be generated in vitro, through oncogenic reprogramming of human somatic cells, using defined components. When injected in mice, in vitro-generated CSCs, like clinically-derived CSCs, form hierarchically-organised tumours, in which a small subset of self-renewing cells maintain tumour growth while generating differentiated progeny with limited proliferative capacity. This is a significant breakthrough as it allows to generate, analyse and perturb in a controlled fashion homogenous populations of CSCs, thus overcoming major obstacles that have so far hampered molecular characterisation of clinically-derived CSCs and limited our understanding of their biology.

Using in vitro-generated CSCs, in combination with mouse models and the analysis of clinical samples, we aim to identify epigenetic mechanisms which affect CSC formation and function by interfering with cellular differentiation programs.  To do so, we are pursuing three complementary lines of investigation:

Epigenetics and intratumour functional heterogeneity

In many cancers, only small subsets of cells are endowed with unlimited proliferative potential and are responsible for maintaining tumour growth, whereas the rest of the cells display a more differentiated phenotype and only have limited ability to proliferate. The molecular basis underlying the functional differences among subpopulations of tumour cells are at present unclear.

Since CSCs generate their non-tumorigenic progeny through a differentiation process, epigenetic mechanisms are likely to play a critical role in defining the malignant phenotype of a cancer cell within a growing tumour (Figure 1).

We are employing genome-wide mapping approaches (ChIP-Seq and FAIRE-seq) to characterise the chromatin landscape of CSCs and identify epigenetic features which distinguish them from the rest of the tumour. By combining these studies with in vivo gain- and loss-of function experiments and analysis of publicly available datasets from cancer patients, we aim to identify epigenetic features which are critical for CSC function and can be modulated for therapeutic purposes. 

Extracellular signalling, chromatin and cancer cell plasticity

Interactions of cancer cells with the tumour microenvironment strongly affect cancer development. These interactions are mediated by extracellular signalling and they are likely to result in epigenetic changes that affect the differentiation status of cancer cells.

We are using mouse models of various cancer types to assess how chromatin affects cancer cell plasticity in response to extracellular signalling. By characterising functional interactions between upstream components of oncogenic signalling pathways and chromatin-related proteins, we aim to understand how cell-to-cell interactions occurring during cancer development are translated into changes in gene expression and modulation of malignant cellular properties.

Oncogenic reprogramming and CSCs formation

In many cancers, CSCs arise through reprogramming of committed cells which lose their cellular identity and acquire self-renewal ability. Thus, alterations in proteins involved in maintenance of epigenetic memory are likely players in the genesis of CSCs.

We are currently performing unbiased, CRISPR/Cas9-based, loss-of-function screens targeting proteins involved in establishment and recognition of DNA methylation patterns, writer, readers and erasers of chromatin marks, chromatin remodelers and proteins controlling the high-order structure of chromatin, in order to identify epigenetic regulators which either prevent (tumour suppressors) or promote (therapeutic targets) the appearance of CSCs.

Paola Scaffidi

paola.scaffidi@crick.ac.uk
+44 (0)20 379 61325

  • Qualifications and history
  • 2002 PhD, Dibit San Raffaele Scientific Institute, Milan, Italy.
  • 2002 - 2007 Postdoctoral Fellow, Cell Biology of Genomes Group, NCI, NIH, USA
  • 2007 - 2013 Staff Scientist, Cell Biology of Genomes Group, NCI, NIH, USA
  • 2014 Established lab at the London Research Institute, Cancer Research UK
  • 2015 Group Leader, the Francis Crick Institute, London, UK