Amelio Programme

Research Programme: Epigenetic Regulation of p53 tumour suppression
Principal Investigator: Prof. Ivano Amelio

Scientific Interests
Genetic and non-genetic factors equally contribute to cancer progression and therapy resistance. Understanding the basis of how integration of intrinsic and extrinsic factors contribute to the cancer pathogenesis is of pivotal importance to unveil clinically relevant tumor vulnerabilities. Ivano’s research mainly focused the understanding the mechanisms of integration of micro-environmental factors and tumour suppressors signalling during tumorigenesis, with a particular focus on the role of p53 family. His major contributions include the identification of specific functions for p53 family members in cellular stress response, mediated by p73 regulation of cancer metabolism (Marini et al, PNAS 2018, Amelio et al, Oncogene, 2013; Amelio et al, TiBS 2014), angiogenesis (Amelio et al, PNAS 2015; Amelio & Melino TiBS 2015) and development (Amelio et al PNAS 2020). He has also been exploring the interplay of p53 signalling under hypoxia, revealing a novel gain-of-function effect of p53 mutants in hypoxic tumours (Amelio et al. PNAS 2018). Overall his work has contributed to the dissection of p53 and its family members in their role of molecular hub for the response to stressors. 

Current Research Direction
A tight relationship between cancer genetics and epigenetics exists. The maintenance of epigenomic integrity is indeed a prerequisite to prevent genomic instability; these two processes are often associated during cancer progression. Constitutive heterochromatin is a major component of the eukaryotic genome, typically situated at pericentromeric and telomeric regions, which includes repetitive satellite DNA and mobile elements such as retro-transposons. Perturbation of the fine balance between epigenetic maintenance of the constitutive heterochromatin and mitosis, DNA repair and replication indicates that dysfunctional constitutive heterochromatin can have far-reaching consequences for genome integrity and tumorigenesis.

Although p53 mutations are strongly associated with aggressive phenotypes (metastasis/therapy resistance), within intra-tumour heterogeneity, not all the p53 mutated tumour subclones display the same phenotypes, indicating that additional factors are involved. It is now evident that disease progression arises not only from genetic evolution and heterogeneity but also from epigenomic alterations that contribute to tumour plasticity and the acquisition of an aggressive phenotype.

The classic functions of p53 in response to acute DNA-damage signals are cell cycle arrest and/or apoptosis. Conversely, however, despite the large volume of literature, experimental evidence has demonstrated that these mechanisms are dispensable for p53-mediated genomic integrity and tumour suppression. Mouse models selectively lacking p53-mediated cell cycle arrest and/or apoptosis (Trp5325,26 mice and p21-/-; Puma-/-; Noxa-/- mice) display efficient suppression of tumour development, mediated by unidentified p53 downstream effectors. Thus, the mechanisms underlining p53-dependent maintenance of genome integrity remain fundamentally unclear. 

We aim to assess a causative relationship between p53 status and epigenetic maintenance of constitutive heterochromatin, in order to identify the last steps of the evolution of cancer to a therapy-resistant and metastatic phenotype. This information will help in defining how cancer evolves to a lethal disease and will suggest potential innovative therapeutic approaches for the treatment of advanced tumours. The major outcome of this programme will be:

Task 1:   Identify epigenetic mechanisms responsible for p53-mediated tumour  suppression
Task 2:  Identify of epigenetic vulnerabilities in cancer cells associated with p53 status
Task 3:   Develop new therapeutic strategies of epigenetic drugs with immuno-checkpoint blockade.

Relevance for Cancer
Although the survival outcomes of patients with cancer have been steadily improving, the majority of patients with advanced-stage and/or high-risk cancers continue to die as a result of metastatic disease. The identification of a causative relationship between p53 status and epigenetic maintenance of constitutive heterochromatin will help in defining the evolution of cancer to a therapy-resistant and metastatic phenotype. This information will direct this research and future research in new strategies to treat advanced cancer and overcome resistance.

p53 prevents constitute heterochromatin relaxation. p53 deficient pancreatic cancer cells (KPflC) display hallmarks of constitute heterochromatin relaxation upon treatment with DNA demethylating agents AZA-cytidine. p53 proficient cells (KC) trated with AZA maintain the structure of their chromocenters. H3K9me3: tri-methylation of Lysine 9 of Histone H3; HP1: heterochromatin protein 1.