Team Leader
What we do
Our group aims to understand the molecular mechanisms that cancer cells hijack to become malignant. One such mechanism is epigenetics. Epigenetics encompasses all the molecular changes that occur at the DNA level of a cell that do not actually affect the DNA sequence but do have a direct impact on gene expression to specify that cell’s fate.
Epigenetic mutations and epigenetic therapies
Cancer cells show aberrations in their epigenome and in proteins that affect the epigenome. This results in the inappropriate overexpression of oncogenes and the silencing of tumour suppressor genes. We are investigating the precise mechanisms underlying the development of epigenetic-driven childhood cancers, with the aim of designing novel epigenetic-based therapies based on the specific epigenetic profile of each child with cancer.
Cancer and the tumour microenvironment
Tumours are not only made up of cancerous cells, but also contain normal cells of different origins. These form what is known as the tumour microenvironment (TME) and mainly consists of immune cells, fibroblasts and endothelial cells. The interaction between the TME and cancer cells is critical in tumour progression and metastasis, thus targeting these cells is a very compelling therapeutic approach.
Our group is investigating how the epigenome of the cells that make up the TME is re-shaped to promote the metastatic capabilities of cancer cells. Our overarching aim is to use epigenetic-based drugs to specifically target malignant pathways that are activated in the cells from the TME. For example, one of our major interests is to use epigenetic drugs as a new immune therapeutic approach, or in combination with existing checkpoint inhibitors.
Our aims
The overall aims of our team are to:
- Characterise the changes in the epigenome and transcriptome that occur during carcinogenesis.
- Identify the key epigenetic drivers in this process.
- Identify key cell populations in the TME whose epigenome is altered.
- Apply this knowledge to the design of novel epigenetic-based therapies.
Research projects
Understanding the epigenetic landscape of DIPG
Contact: Fa Valdes Mora, FValdesMora@ccia.org.au
Diffuse intrinsic pontine glioma (DIPG) is the most aggressive brain tumour in children, with a median post-diagnosis survival time of approximately one year. Recent studies have identified that in more than 60% of DIPG cases, a somatic mutation of the H3F3A gene leads to a lysine 27 to methionine mutation at the histone variant H3.3 (H3.3K27M). Mechanistic studies on how this mutation affects chromatin, gene expression and oncogenesis are currently underway but far from complete.
Our team aims to investigate how H3.3K27M mutation affects the epigenome and how it interacts with other epigenetic factors, with the aim of using epigenetic drugs to therapeutically target the downstream epigenetic consequences of H3.3K27M presence.
Epigenetic therapy to target malignant cells
Contact: Fa Valdes Mora, FValdesMora@ccia.org.au
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of tumour-infiltrating immune myeloid progenitors that promote cancer progression and metastasis in many cancer types. Using a preclinical mouse model, we have discovered a transcriptional program that results in malignant recruitment and activation of MDSCs leading to metastasis. It has also been shown that abatement of MDSCs dramatically reduces metastasis. However, due to the high heterogeneity of MDSCs, the phenotype of the pro-metastatic/malignant MDSCs and the underlying mechanisms of their recruitment, expansion and differentiation are still unknown, making MDSC-targeted strategies elusive.
Epigenetic therapy is able to up-regulate immune signalling pathways in epithelial cancer cells, and epigenetic drugs have been found capable of priming and sensitising the host immune response to subsequent immunotherapy. Thus combined epigenetic and immunotherapy holds significant promise for improving patient outcomes. Our team aims to identify the epigenetic characteristics of malignant MDSCs in cancer, to enable the design of epigenetic drugs that can modify MDSCs towards differentiated phenotypes and thus disable their immune suppressive capacity. A combinatorial treatment strategy with epigenetic drugs could sensitize cancers to current immunotherapy.
Team
Team Leader
Research Officer
Yolanda Colino Sanguino
PhD Student
Laura Rodriguez de la Fuente
Honours Student
Dana Kisswani
Get in touch
Do you have a question about our work? For any enquiries please don’t hesitate to contact us.
