Welcome to Leonardo A. Meza-Zepeda's project group Translational Genomics
The translational genomics group aims to understand cancer genome biology, by studying the genetic and epigenetic events that control gene expression in cancer. We aim to identify and characterise key regulatory machanisms, molecules and pathways that play a role in tumour development and progression, with the ultimate goal to translate this genomic knowledge to improve patient treatment and care.
Throughout the years our group has pioneered the establishment of numerous microarrays and high-throughput sequencing based methods to study genome structure, dynamics and function at a high-throughput level. Together with bioinformatics approaches, we integrate large genome-wide data sets to identify mechanisms that regulate gene expression, and drivers of tumourigenesis. Some of these candidates are further validated using different functional assays. Our work can be divided in three main areas.
Preclinical models are important tools for basic and translational research. Using cell lines and xenografts we study how aberrations in DNA copy number and methylation translate into aberrant mRNA and miRNA expression in bone (osteosarcomas) and adipose (liposarcomas) tissue tumours. Using a large cohort of preclinical models we aim to identify driver events of sarcoma development, which are further validated using clinical samples, as well as functional studies. The preclinical models are extensively characterised at the genome, transcriptome and methylome level, which is complemented with exome and full-genome sequencing. These preclinical models represent a valuable tool for functional and translational studies, and represent models for subsequent drug testing and validation of driver cancer genes. The characterisation of model systems is performed for different tumour forms generating unique resources and information for further translational studies.
Characterisation of preclinical models is performed in the context of studying fusion genes and transcripts, mechanisms of drug resistance and targeted resequencing for identification of new druggable targets.
During the last years we have established a number of high-throughput sequencing technologies to study tumours and biological systems, some of which we are currently implementing in translational studies. Our translational projects involve the collaboration between different clinical departments, including Oncology, Surgery and Pathology, and our genomic team. Currently we are establishing a personalised cancer biomarkers prospective study to monitor disease evolution together with the Cancer Clinic and Pathology. Mutation-based personal biomarkers will be used to detect and monitor circulating tumour DNA in plasma throughout the patient treatment and correlated with disease progression and treatment. The project aims to develop a less-invasive and sensitive way of monitoring disease through direct monitoring of circulating tumour DNA in plasma (liquid biopsies).
We also participate in different collaborative efforts for identifying new druggable targets in different cancer types using exome or targeted resequencing. We have started a pilot study for identifying new drug targets in lung cancer, aiming to identify recurrent tumour-specific mutations that may represent novel targets for therapeutic. Using a similar approach, but at a National level, I’m a PI of the Norwegian Cancer Genomics Consortium, a large national research project that will evaluate the use of genomic-based strategies for precision medicine.
The biology of differentiation
Cancer can be seen as the result of differentiation and proliferation getting out of balance, and for this reason it is also important to understand how normal biology is controlled to be able to identify aberrations in cancer. We are therefore, with the aim to identify mechanisms involved in osteosarcoma development, studying the biology of bone differentiation, specifically the genetic and epigenetic mechanisms that control the differentiation program from an adult stem cell to an osteoid matrix-producing cell. Using in vitro bone marrow stem cell models and primary cultures, we aim to better understand how changes in transcription factors and chromatin conformation affects gene expression, and correlate these changes with the ones observed in bone tumours.
I'm also head of the Helse Sør-Øst and University of Oslo Genomics Core Facility.