Paola Scaffidi

 

Epigenetic mechanisms of cancer development

Epigenetic mechanisms have emerged as key players in cancer development which affect cellular states at multiple stages of the disease. During carcinogenesis, alterations in chromatin and DNA methylation resulting from genetic lesions unleash cellular plasticity and favour oncogenic cellular reprogramming. At later stages, during cancer growth and progression, additional epigenetic changes triggered by interaction with the microenvironment modulate cancer cell phenotypes and properties, and shape tumour architecture [1].

Our laboratory is interested in uncovering novel epigenetic mechanisms of cancer development and thereby guiding the development of novel therapeutic strategies. In particular, we aim to understand:

•          How disruption of epigenetic memory promotes acquisition of uncontrolled cellular self-renewal during tumorigenesis.

•          How epigenetic mechanisms generate functional diversity within individual tumours.

•          How cancer cells reprogram their epigenome and hijack normal epigenetic regulators to sustain - and enhance - their malignant phenotypes.

To address these questions we use cellular model systems in combination with mouse studies and the analysis of clinical samples [2-4].

Projects the student may work on and actively develop include:

1) Investigation of cell non-autonomous mechanisms of cancer development promoted by disruption of epigenetic control. The student will study the relationship between cell-intrinsic (mutations in epigenetic regulators) and cell-extrinsic (altered cell-to-cell interactions) mechanisms, and investigate its effect on clonal dynamics within tumours and its role in driving cancer evolution.

2) CRISPR/Cas9-based functional screening to identify novel epigenetic targets for cancer treatment. The student will use a custom-made sgRNA library targeting most known epigenetic regulators to identify and characterize proteins exploited by cancer cells to seed efficient metastasis.

 3) Characterization of the molecular mechanism linking a specific type of histone acetylation and maintenance of cancer cell self-renewal. This project focuses on a protein complex that we have identified as an important regulator of cancer stem cell function through an unbiased screen. The student will use a combination of molecular and cellular approaches to understand how cancer cell co-opt this protein complex to sustain their malignant properties. The functional importance of this complex, combined with the scarce knowledge of its mode of action, makes it a particularly attractive subject of investigation for both basic science and translational purposes.    

All potential projects involve a broad range of techniques including CRISPR-mediated genome editing, microscopy and quantitative image analysis, flow cytometry, mouse transplantation assays or use of transgenic animals, and genome-wide biochemical techniques (ChIP-seq, RNA-seq).

Applicants should note that the laboratory is not directly translational, and a strong interest in basic understanding of cancer is critical to join the group.

Only one studentship is available with this group and the precise project will be decided upon in consultation with the supervisor.

1. Wainwright, E. N. and Scaffidi, P. (2017)
Epigenetics and cancer stem cells: Unleashing, hijacking, and restricting cellular plasticity.
Trends in Cancer  3: 372-386. PubMed abstract

2. Morales Torres, C., Biran, A., Burney, M. J., Patel, H., Henser-Brownhill, T., Cohen, A.-H. S., Li, Y., Ben-Hamo, R., Nye, E., Spencer-Dene, B., Chakravarty, P., Efroni, S., Matthews, N., Misteli, T., Meshorer, E. and Scaffidi, P. (2016)
The linker histone H1.0 generates epigenetic and functional intratumor heterogeneity.
Science  353: aaf1644. PubMed abstract

3. Scaffidi, P. and Misteli, T. (2011)
In vitro generation of human cells with cancer stem cell properties.
Nature Cell Biology  13: 1051-1061. PubMed abstract

4. Fernandez, P., Scaffidi, P., Markert, E., Lee, J.-H., Rane, S. and Misteli, T. (2014)
Transformation resistance in a premature aging disorder identifies a tumor-protective function of BRD4.
Cell Reports  9: 248-260. PubMed abstract